Pharmacology and Neurotransmitters of the Autonomic Nervous System

#### **Chapter 1**

## Neurotransmitters of Autonomic Nervous System

*Zeynep Balaban and Gokhan Kurt*

#### **Abstract**

Autonomic nervous system (ANS) regulates the physiologic process in the body and has essential role in the systems such as blood pressure regulation, respiration, heart rate, and sexual arousal. ANS is divided into the sympathetic nervous system and the parasympathetic nervous system and regulates whole organism functions in the body. Although the main neurotransmitters in the ANS are norephinephrine, epinephrine, and acetilcholine, many other different agents and chemicals play an important role of the neurotransmitters function. These molecules act on many different receptors and sides. This chapter provides a detailed evaluation of neurotransmitters, related molecules, their receptors and how they function to maintain autonomic functions in both the central and peripheral parts of the systems.

**Keywords:** neurotransmitter, receptor, sympathetic, parasympathetic, physiology, cholinergic

#### **1. Introduction**

The autonomic nervous system (ANS) is a complex network of nerves responsible for regulating involuntary body functions such as heart rate, blood pressure, bladder function, digestion, and respiration. The ANS is divided into two main branches: the sympathetic nervous system and the parasympathetic nervous system, both of which use different neurotransmitters to carry out their functions. The sympathetic nervous system is responsible for initiating the "fight or flight" response by increasing heart rate and blood pressure, dilating the pupils, and redirecting blood flow from the digestive system to the muscles. This reaction is triggered in response to perceived threats and prepares the body for action. Conversely, the parasympathetic nervous system slows the heart rate and respiration, constricts the pupils, and increases blood flow to the digestive system. This results in a "rest and digest" response, that promotes relaxation and facilitates recovery from stress. The ANS is critical to maintaining homeostasis by balancing body functions and adapting to changes in the environment. It regulates several vital activities that are important for survival and helps us respond appropriately to different situations [1].

Neurotransmitters are the crucial mediators of interneuronal communication, responsible for transmitting signals between neurons and their target cells. On the website ANS, several neurotransmitters have been discovered, each with unique functions and roles, including acetylcholine, norepinephrine, dopamine, serotonin, and

neuropeptides [1]. In recent years, numerous neurotransmitters have been discovered to be involved in signal transduction, revealing the complicated and multifaceted nature of autonomic regulation. This chapter will review some of the recent discoveries in this field and highlight the functions and mechanisms of action of some important neurotransmitters.

Recent discoveries have shown that the ANS is organized in complex ways and that the function and structure of non-synaptic autonomic neuroeffectors is a crucial aspect of ANS regulation. In addition to classical neurotransmission, the concept of co-transmission has been introduced, in which multiple neurotransmitters can be released from a single neuron [2]. In addition, neuromodulation is another important concept in neuroscience that has contributed significantly to our understanding of ANS. Neuromodulators are chemicals that alter the activity of neurotransmitters and their receptors, thereby modulating the strength and efficacy of synaptic transmission [3]. Both co-transmission and neuromodulation are essential for the flexible and dynamic regulation of physiological processes and enable ANS to respond rapidly and appropriately to changes in the internal and external environment [2, 3]. Thanks to advances in molecular biology and imaging techniques, we can study these processes in great detail and gain insight into the complex mechanisms underlying autonomic neurotransmission.

#### **2. Neuroeffector junction**

The autonomic neuromuscular junction (ANMJ) is a specialized synapse where autonomic nerve impulses are transmitted to effector cells such as smooth muscle, cardiac muscle, and glands. Unlike the skeletal neuromuscular junction, the ANMJ lacks pre- and post-functional specialization. It has varicosities that release neurotransmitters during impulse transmission [4]. The structure of the ANMJ may vary depending on the type of effector cell. In smooth muscle cells, neuromuscular junctions are diffuse and distributed over a large area. In cardiac muscle cells, the neuromuscular junctions are located in the intercalated discs between adjacent cells. In glandular cells, the neuromuscular junction sites are located at the cell membrane. The ANMJ facilitates the transmission of nerve impulses through the release of neurotransmitters from the presynaptic neuron, the diffusion of these neurotransmitters across the synaptic cleft, and the activation of post-synaptic receptors on the effector cell. Acetylcholine and norepinephrine are the two major neurotransmitters involved in ANMJ [1, 5]. Acetylcholine is the neurotransmitter released by both preganglionic and post-ganglionic neurons of the parasympathetic division. It acts on muscarinic receptors in effector cells and causes smooth muscle cell contraction, slowing of heart rate in cardiac myocytes, and secretion of glandular cells [6]. In the sympathetic nervous system, norepinephrine is the neurotransmitter released by post-ganglionic neurons. Norepinephrine acts on alpha- and beta-adrenergic receptors in effector cells and leads to contraction of smooth muscle cells, acceleration of heart rate in cardiac muscle cells, and secretion of glandular cells [7].

The ANMJ effectors are muscle bundles connected by low-resistance pathways that allow electrotonic propagation of activity within the smooth muscle bundle. Varicosities are constantly in motion and have a dynamic relationship with muscle cell membranes, which means that a given impulse is likely to trigger transmitter release from only some of the varicosities it encounters. In addition, neurotransmitters such as dopamine, serotonin, and histamine may also be released at the ANMJ

*Neurotransmitters of Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.112007*

and modulate its activity. In addition, other substances such as hormones, locally released agents, and neurotransmitters from nearby nerves can also alter neurotransmission by affecting either the release or the action of the transmitter. Many of these substances, including co-transmitters, are capable of affecting neuronal growth and development. Because the autonomic neuroeffector junctions have a wide and variable gap, they are particularly suitable for the above mechanisms of neuronal control [8].

#### **3. Signaling molecules and their receptors**

Neurotransmitters are molecules released by nerves in response to electrical stimulation that bind to specific receptors on neighboring cells to produce a response. For a substance to be classified as a neurotransmitter, it must meet certain criteria, such as being synthesized and stored by the presynaptic neuron, being released in a calcium-dependent manner, having a mechanism to terminate release, and producing effects similar to those of electrical nerve stimulation when applied locally [9]. Although early studies identified only a few neurotransmitters in the ANS, more recent research has identified several substances, such as monoamines, amino acids, neuropeptides, ATP, nitric oxide (NO), and carbon monoxide (CO) [10, 11].

Neurons can store and release various neurotransmitters and neuromodulators that can have different effects on target cells. Neurons can have both slow-acting neuropeptide transmitters and fast-acting small molecule transmitters that can be present in the same neurons and released through co-localized synaptic vesicles, or they can be stored in different groups of vesicles to transmit signals together (**Table 1**) [12].

Research has also shown that neurotransmitters can have multiple functions within the ANS. Acetylcholine, for example, was previously thought to be exclusively responsible for parasympathetic signaling, whereas norepinephrine was thought to be responsible for sympathetic signaling. However, acetylcholine can also be released from sympathetic neurons and act as a modulator of sympathetic activity [6].

ANS has two types of receptors: cholinergic and adrenergic. Acetylcholine activates the cholinergic receptors, while catecholamines such as epinephrine and norepinephrine activate the adrenergic receptors. Cholinergic receptors are divided into two categories: nicotinic receptors and muscarinic receptors. Nicotinic receptors are mainly located in the autonomic ganglia and neuromuscular junction, whereas muscarinic receptors are located in the effector organs of the PNS and some tissues innervated by the SNS. Adrenergic receptors are divided into alpha and beta receptors. Alpha receptors have two subtypes, alpha-1 and alpha-2 receptors. Alpha-1 receptors are located in the smooth muscle of blood vessels and in the iris of the eye, while alpha-2 receptors are located in presynaptic neurons and inhibit the release of norepinephrine. Beta receptors are also of two subtypes, beta-1 and beta-2 receptors. Beta-1 receptors are located in the heart, while beta-2 receptors are found in lung smooth muscle and skeletal muscle. ANS has regulatory systems such as self-inhibition of norepinephrine release via presynaptic alpha-2 receptors, regulation of norepinephrine synthesis, and desensitization and hypersensitization of adrenoceptors. Acetylcholine acts on two classes of receptors: nicotinic receptors, found mainly in ganglia, and muscarinic receptors, which are coupled to G proteins and respond more slowly. Among purine receptors, there are two main types: P1 receptors, which are sensitive to adenosine and blocked by methylxanthines, and P2 receptors, which are sensitive to ATP and can lead to prostaglandin synthesis.


*Some neurotransmitters can be both excitatory and inhibitory depending on the receptor to which they bind, and their functions can vary depending on the specific location and target of the autonomic nervous system.*

#### **Table 1.**

*Neurotransmitters of the Autonomic Nervous System.*

Neuropeptide receptors are G protein-coupled receptors that activate adenylyl cyclase or phospholipase C as signal transducers [13–15].

#### **3.1 Acetylcholine**

Acetylcholine is a chemical messenger produced by neurons in various parts of the nervous system. It is released by large pyramidal cells in the motor cortex, various neurons in the basal ganglia, and motor neurons controlling skeletal muscles, among others. Acetylcholine usually has a stimulatory effect on nerve cells, but it can also inhibit certain peripheral parasympathetic nerves, such as those that slow the heart. Choline acetyltransferase (ChAT) is the enzyme responsible for the synthesis of acetylcholine from choline and acetyl coenzyme A in the cytoplasm of nerve cells. After production, acetylcholine is stored in tiny vesicles that have a specific transporter in their membrane. When electrical signals trigger the release of calcium ions, acetylcholine is released into the synaptic cleft, where it can bind to receptors on nearby cells. Acetylcholinesterase is an enzyme that breaks down acetylcholine, limiting its action. The breakdown of acetylcholine produces choline, which is then transported back into neurons to form more acetylcholine. The uptake of choline into the presynaptic terminal is a crucial step in the production of acetylcholine [6].

#### **3.2 Norepinephrine**

The neurotransmitter norepinephrine is synthesized by three enzymes and released by neurons in the brainstem and hypothalamus, particularly in the locus ceruleus of the pons. Terminals of these neurons release norepinephrine into the extracellular space by exocytosis triggered by electrical stimulation and a Ca2+ dependent process. Norepinephrine is stored in small and large dense nuclear vesicles in the neuronal cytosol alongside chromogranins and dopamine-β-hydroxylase. Its action is rapidly terminated when it interacts with specific receptors by being recycled into neuronal nodes or non-neuronal cells. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) metabolize norepinephrine in intracellular

*Neurotransmitters of Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.112007*

cells. Norepinephrine controls overall activity and mood of the mind by transmitting nerve fibers to different brain areas, resulting in increased alertness. In most of these areas, norepinephrine activates excitatory receptors, although in some regions it triggers inhibitory receptors instead. The post-ganglionic neurons of the SNS secrete NE, which has both excitatory and inhibitory effects on various organs [1, 16].

#### **3.3 ATP**

Adenosine triphosphate (ATP), a type of purine nucleotide, was originally identified as the first neurotransmitter in nonadrenergic noncholinergic (NANC) nerves that met the criteria for a neurotransmitter. Further research has shown that purinergic signaling is widespread in both neural and non-neural systems. ATP acts as a neurotransmitter at neuroeffectors, synapses in peripheral autonomic ganglia, and in the brain and spinal cord. It also plays a critical role as a signaling molecule in the enteric nervous system and on sensory nerves affecting both physiological reflexes and nociception. ATP is synthesized in nerve terminals and stored in vesicles. Once released, it binds to post-functional P2X ion channel receptors and is rapidly cleaved by ectonucleotidases into adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine. Adenosine is then transported back into neurons and non-neuronal cells via a high-affinity nucleoside carrier uptake system. It can be converted back to ATP and returned to vesicles or further degraded by adenosine deaminase to inosine, which is inactive and enters the bloodstream. Adenosine acts on prefunctional P1 receptors and inhibits neurotransmitter release. In addition, small amounts of other nucleotides such as ADP, AMP, guanosine triphosphate (GTP), uridine triphosphate (UTP) and diadenosine polyphosphates have been detected in synaptic vesicles, which may also have a neuromodulatory function in the nervous system [3, 17].

#### **3.4 Nitric oxide**

NO is a putative neurotransmitter in the ANS that is synthesized in a reaction in which L-arginine is converted to L-citrulline by nitric oxide synthase (NOS). Unlike other neurotransmitters, NO is not stored in vesicles but is synthesized almost instantaneously on demand and diffuses from presynaptic terminals to act on intracellular guanylate cyclase in the post-synaptic neuron, resulting in relaxation. Type I NOS, which is constitutively expressed in autonomic neurons, is stimulated by Ca2+ during transmission. NO does not act on extracellular receptors but rather at intracellular sites, and its unstable nature allows it to terminate NO-dependent responses without the need for degradative enzymes or reuptake. In addition, NO can readily bind to the heme group of hemoglobin and inhibits NO-dependent reactions. Nitric oxide is not only found in the autonomic nervous system, but is also produced by nerve terminals in brain regions responsible for long-term behavior and memory. Its unique mechanism of formation in the presynaptic terminal and its action on the post-synaptic neuron distinguish it from other small molecule transmitters. NO is synthesized almost immediately and diffuses out of the presynaptic terminals within seconds rather than being released in vesicular packets. Once in the post-synaptic neuron, it does not significantly alter membrane potential but modifies intracellular metabolic functions to alter neuronal excitability for seconds, minutes, or possibly even longer. Therefore, NO could shed light on previously unexplained behavioral and memory functions [18, 19].

#### **3.5 Other neurotransmitters**

The ANS uses several neurotransmitters to regulate various physiological functions. One of these neurotransmitters is 5-hydroxytryptamine (5-HT), which is synthesized from tryptophan via 5-hydroxytryptophan by tryptophan hydroxylase and l-aromatic amino acid decarboxylase. Hydroxytryptamin (HT) While 5-hydroxytryptophan is primarily synthesized in myenteric neurons, it can also act as a spurious neurotransmitter after being taken up and released by sympathetic nerves. Similarly, dopamine, GABA, and glutamate, which are classic neurotransmitters in the central nervous system, also act as autonomic neurotransmitters. GABA is the major inhibitory neurotransmitter in the adult central nervous system and is secreted by nerve terminals in the spinal cord, cerebellum, basal ganglia, and many areas of the cortex. The role of GABA in enteric neurotransmission has been identified, where it acts through excitatory GABAA and prefunctional inhibitory GABAB receptors. Dopamine is secreted by neurons from the substantia nigra, terminating mainly in the striatal region of the basal ganglia. Its action is primarily inhibitory. Glutamate is secreted from presynaptic terminals in many sensory pathways entering the central nervous system and in many areas of the cerebral cortex and is known to cause excitation. Serotonin, secreted by nuclei in the median raphe of the brainstem, acts as an inhibitor of pain pathways in the spinal cord and contributes to mood control and sleep initiation in higher regions of the nervous system [1, 20].

#### *3.5.1 Hydrogen sulfide (H2S)*

H2S is a colorless, flammable gas that has long been known as a toxic environmental pollutant. However, recent studies have shown that H2S is also an endogenously produced gasotransmitter that plays a crucial role in various physiological processes in the body. H2S is produced by the enzyme cystathionine beta synthase as part of the transsulfuration pathway that converts homocysteine to cysteine. Another enzyme, cystathionine gamma lyase, can also produce H2S from cysteine. The third H2S-producing enzyme, 3-mercaptopyruvate sulfurtransferase, produces H2S from 3-mercaptopyruvate. H2S can also be produced by the gut microbiota, which metabolizes sulfur-containing amino acids. Once produced, H2S acts as a signaling molecule that regulates various physiological processes, including blood pressure, inflammation, and cell signaling. H2S has also been shown to have anti-inflammatory, antioxidant, and cytoprotective effects. One of the most important physiological processes regulated by H2S is vasodilation, which contributes to the regulation of blood pressure. H2S induces vasodilation by activating ATP-sensitive potassium channels in vascular smooth muscle cells. This leads to hyperpolarization of the cell membrane, resulting in smooth muscle cell relaxation and subsequent vasodilation. H2S also has an anti-inflammatory effect. It can inhibit the production of pro-inflammatory cytokines such as interleukin-1 beta (IL-1B), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6). This anti-inflammatory effect is thought to be mediated by inhibiting the activation of nuclear factor kappa B (NF-kB), which is an important regulator of the inflammatory response. In addition, H2S has been shown to have a cytoprotective effect. It can protect cells from oxidative stress-induced damage and apoptosis. H2S can also increase the activity of antioxidant enzymes such as superoxide dismutase and catalase, which also contributes to its cytoprotective effect. Overall, H2S is a gasotransmitter that plays a crucial role in regulating various physiological processes in the body. Its vasodilatory, anti-inflammatory, and cytoprotective effects

make it a promising therapeutic target for the treatment of various diseases such as hypertension, inflammation, and oxidative stress-related disorders [21, 22].

#### *3.5.2 Neuropeptide Y*

NPY is a 36 amino acid neuropeptide widely distributed in the central and peripheral nervous system. It belongs to the peptide family, which also includes peptide YY (PYY) and pancreatic polypeptide (PP). NPY acts as a neurotransmitter in the brain, where it is involved in a number of physiological functions, including appetite regulation, stress response, anxiety, and mood regulation. NPY is also found in the peripheral nervous system, where it regulates cardiovascular function, gastrointestinal motility, and immune function. In humans, the NPY gene is located on chromosome 7, and the peptide is synthesized in the cell bodies of neurons in the brain and peripheral nervous system. NPY is released by nerve terminals in response to a variety of stimuli, including stress, fasting, and exercise. NPY exerts its effects by binding to a family of G protein-coupled receptors called Y receptors. There are five known Y receptors (Y1, Y2, Y4, Y5, and Y6), each of which has a different distribution pattern in the brain and peripheral tissues. The Y1 receptor is the most abundant subtype in the brain and is involved in the regulation of feeding behavior, anxiety, and pain perception. The Y2 receptor is also found in the brain and is involved in modulating the release of neurotransmitters. The Y4 and Y5 receptors are mainly found in the periphery, where they regulate food intake, adiposity, and glucose homeostasis. The Y6 receptor is expressed in the brain, but its function is not well understood. NPY is associated with a number of human diseases, including obesity, diabetes, anxiety, and cardiovascular disease. In obesity, elevated levels of NPY have been observed, leading to increased food intake and weight gain. In diabetes, NPY has been shown to play a role in regulating glucose homeostasis, and drugs targeting the Y2 receptor have been suggested as potential therapies [23–25].

#### *3.5.3 Orexin*

Another recently discovered ANS neurotransmitter is orexin, also known as hypocretin. It is a neuropeptide produced mainly in a small group of neurons in the hypothalamus of the brain. This neuropeptide plays an important role in regulating various physiological processes, including sleep, wakefulness, feeding behavior, energy homeostasis, and reward systems.

Orexin was first discovered in 1998, and since then, extensive research has been conducted to understand its functions in the brain. One of the most important roles of orexin is its involvement in sleep regulation. Orexin neurons are active during periods of wakefulness and promote wakefulness by stimulating the release of other neurotransmitters such as dopamine, norepinephrine, and histamine. These neurotransmitters ensure that the brain remains in a state of arousal and alertness. In addition, orexin has been found to play a critical role in regulating feeding behavior and energy homeostasis. Orexin promotes feeding behavior by increasing appetite and enhancing the rewarding properties of food. This neuropeptide also regulates energy expenditure by increasing thermogenesis, or heat production, in brown adipose tissue. Studies also suggest that orexin may be involved in the development of addiction and drug-seeking behavior. This neuropeptide has been found to enhance the rewarding effects of drugs such as cocaine and amphetamines by stimulating the release of dopamine in the brain's reward centers. In addition, recent studies have

shown that orexin may play a role in regulating emotional behaviors such as anxiety and depression. Orexin signaling has been found to be disrupted in people with anxiety and depressive disorders, and modulation of orexin signaling has been suggested as a potential therapeutic target for these disorders [26, 27].

#### *3.5.4 PACAP*

Pituitary adenylate-cyclase-activating polypeptide (PACAP) is a neuropeptide that acts as a neurotransmitter or neuromodulator in the central and peripheral nervous systems. It was first discovered in the hypothalamus, where it has been shown to stimulate the release of adrenocorticotropic hormone from the pituitary gland. Since then, PACAP has been found to have a variety of functions in the nervous system, including regulating the release of neurotransmitters, modulating synaptic plasticity, and maintaining neuronal survival. One of the most important functions of PACAP in the nervous system is the regulation of neurotransmitter release. PACAP has been shown to stimulate the release of several neurotransmitters, including acetylcholine, norepinephrine, and dopamine, from both central and peripheral neurons. This suggests that PACAP may play an important role in regulating autonomic function as well as modulating higher brain functions such as learning and memory. PACAP also plays a critical role in synaptic plasticity, the process by which the strength of synapses between neurons is altered in response to changes in neuronal activity. In particular, PACAP has been shown to enhance long-term potentiation, a form of synaptic plasticity thought to underlie learning and memory. This suggests that PACAP could be an important target for the development of drugs to improve cognitive function. Another important function of PACAP in the nervous system is to maintain neuron survival. PACAP has been shown to protect neurons from a range of damage, including oxidative stress, ischemia, and excitotoxicity [28, 29]. This suggests that PACAP may have therapeutic potential for the treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's disease.

#### *3.5.5 Galanin*

Recent research has identified the neuropeptide galanin as another important ANS neurotransmitter. Galanin is a neuropeptide widely distributed in the central and peripheral nervous system. It was first discovered in the pig intestine in 1983, but later studies showed that it is also expressed in the brain and various other tissues. Galanin is synthesized as a precursor protein and then cleaved into smaller peptides that are released by nerve terminals as neurotransmitters or neuromodulators. Galanin acts on three different G protein-coupled receptors, namely GAL1, GAL2, and GAL3. These receptors are widely distributed in the brain and peripheral tissues, suggesting that galanin has multiple biological effects. In the nervous system, galanin is involved in the regulation of a variety of functions, including feeding, pain perception, memory, and anxiety. One of the most important functions of galanin in the nervous system is its involvement in pain modulation. Galanin has been shown to inhibit the release of substance P, a neuropeptide involved in the transmission of pain signals. Galanin also regulates the activity of nociceptors, the primary sensory neurons that respond to painful stimuli. These effects of galanin suggest that it is a potential therapeutic agent for the treatment of chronic pain. In addition to its role in pain modulation, galanin is also involved in the regulation of feeding behavior. Studies have shown that galanin stimulates feeding behavior in animals, and blocking its activity can lead to decreased

#### *Neurotransmitters of Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.112007*

food intake and weight loss. The GAL1 receptor has been identified as the main mediator of galanin's effects on feeding behavior, making it a potential target for the treatment of obesity. Galanin has also been associated with the regulation of memory and anxiety. Studies have shown that galanin levels are altered in the brains of animals exposed to stress and that administration of galanin can attenuate the behavioral and neurochemical effects of stress. These results suggest that galanin may play a protective role against the negative effects of stress on the brain and that it has potential for treating anxiety [30–32].

#### *3.5.6 Taurine*

Taurine, an amino acid with neuroprotective properties, plays a crucial role in regulating various cellular processes in the central nervous system. Taurine acts as a neuromodulator within the ANS, affecting neuronal excitability and autonomic functions. It has been shown to have a significant impact on neural stem and progenitor cells through modulation of gene expression. Taurine exerts its protective effects by influencing inflammatory processes in the central nervous system, inhibiting apoptosis, acting as an antioxidant, and controlling cell volume and water content in neurons. One of the most important mechanisms by which taurine provides neuroprotection is the suppression of apoptosis or programmed cell death. Taurine acts on both ionotropic taurine receptors and metabotropic taurine receptors to inhibit apoptosis triggered by stress in the endoplasmic reticulum (ER). By attenuating apoptosis triggered by ER, taurine helps to ensure neuron survival and prevent neuronal damage. In addition, taurine has antioxidant properties that effectively scavenge free radicals and reduce oxidative stress in the central nervous system. This antioxidant activity helps protect neurons from oxidative damage and contributes to the overall neuroprotective effects of taurine. The neuroprotective properties of taurine have made it a promising candidate for the prophylaxis and treatment of neurodegenerative diseases [33–37].

#### **4. Conclusion**

The ANS plays a critical role in maintaining homeostasis and regulating physiological functions throughout the body. Neurotransmitters serve as important mediators in the transmission of signals within the ANS and enable precise communication between neurons and their target tissues or organs. In this comprehensive exploration of the neurotransmitters of the autonomic nervous system, we have gained valuable insights into their intricate mechanisms and physiological effects. Recent advances in our understanding of the ANS have been driven by the identification of new neurotransmitters and their functions. These findings have led to a more comprehensive understanding of the complex mechanisms that regulate various physiological processes. The discovery of new ANS neurotransmitters has opened new possibilities for targeted treatments of autonomic disorders. Precise targeting of these neurotransmitters could lead to more effective therapies with fewer side effects than current treatments. In addition, the discovery of new neurotransmitters has shed light on the intricate signal transduction pathways underlying ANS regulation. By studying these pathways, researchers can gain a deeper understanding of how different physiological systems interact to maintain homeostasis in the body. As research in this area continues to advance, we can expect to gain further insight into the functions of ANS

neurotransmitters and their role in regulating physiological processes. These discoveries promise new treatments and therapies for autonomic disorders, as well as a more comprehensive understanding of the complexity of the autonomic nervous system.

### **Author details**

Zeynep Balaban\* and Gokhan Kurt Department of Neurosurgery, Faculty of Medicine, Gazi University, Ankara, Turkey

\*Address all correspondence to: zeynep.balaban@yahoo.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Neurotransmitters of Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.112007*

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[29] Arimura A. Perspectives on pituitary adenylate cyclase activating polypeptide (PACAP) in the neuroendocrine, endocrine, and nervous systems. The Japanese Journal of Physiology. 1998;**48**(5):301-331. DOI: 10.2170/ jjphysiol.48.301

[30] Lundström L, Elmquist A, Bartfai T, Langel U. Galanin and its receptors in neurological disorders. Neuromolecular Medicine. 2005;**7**(1-2):157-180. DOI: 10.1385/NMM:7:1-2:157

[31] Baranowska B et al. Neuropeptide Y, galanin, and leptin release in obese women and in women *Neurotransmitters of Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.112007*

with anorexia nervosa. Metabolism. 1997;**46**(12):1384-1389

[32] Lang R, Gundlach AL, Kofler B. The galanin peptide family: Receptor pharmacology, pleiotropic biological actions, and implications in health and disease. Pharmacology & Therapeutics. 2007;**115**(2):177-207. DOI: 10.1016/j. pharmthera.2007.05.009

[33] Menzie J, Prentice H, Wu J-Y. Neuroprotective mechanisms of taurine against ischemic stroke. Brain Sciences. 2013;*3*:877-907. DOI: 10.3390/ brainsci3020877

[34] Paula-Lima AC et al. Activation of GABAA receptors by taurine and muscimol blocks the neurotoxicity of β-amyloid in rat hippocampal and cortical neurons. Neuropharmacology. 2005;**49**(8):1140-1148

[35] Schaffer S, Kim HW. Effects and mechanisms of Taurine as a therapeutic agent. Biomolecules & Therapeutics. 2018;**26**(3):225-241

[36] El Idrissi A, Trenkner E. Taurine as a modulator of excitatory and inhibitory neurotransmission. Neurochemical Research. 2004;**29**(1):189-197

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#### **Chapter 2**

## Pharmacology of the Autonomic Nervous System

*Redha Waseem, Mogahed Ismail Hassan Hussein, Tayseer Salih Mohamed Salih and Sohel Mohamed Gamal Ahmed*

#### **Abstract**

This comprehensive chapter delves into the intricate landscape of autonomic nervous system (ANS) pharmacology. It meticulously explores both agonists and antagonists pharmacology that work on the sympathetic and parasympathetic divisions. This chapter covers direct and indirectly acting drugs and thoroughly explains receptor interactions. The content spans a wide array of examples, elucidating these agents' mechanisms and clinical applications. Through a detailed examination of pharmacokinetics, metabolism, adverse effects, and contraindications, healthcare professionals gain the insights needed to navigate the complexities of ANS modulation. This knowledge equips practitioners to harness the potential of autonomic drugs, facilitating optimal therapeutic outcomes across diverse medical scenarios.

**Keywords:** pharmacology, autonomic nervous system, sympathetic, parasympathetic, medications

#### **1. Introduction**

The autonomic nervous system (ANS) plays a pivotal role in maintaining homeostasis by modulating various vital processes, including heart rate, blood pressure, respiratory rate, gastrointestinal motility, and glandular secretions [1]. Understanding the pharmacology of the ANS is paramount in medicine, particularly in anesthesia and other acute medical specialities, as it allows healthcare professionals to manipulate autonomic pathways effectively and achieve desirable clinical outcomes [2]. This chapter aims to provide a comprehensive overview of ANS pharmacology, focusing on the sympathetic (SANS) and parasympathetic (PANS) divisions and their associated receptors.

Understanding the receptor selectivity of pharmacological agents is paramount in achieving desired clinical outcomes. Many drugs exhibit selectivity for specific adrenergic or cholinergic receptors, allowing for targeted modulation of the SANS and PANS [3]. Healthcare professionals can manipulate autonomic pathways to optimize patient care by carefully selecting and administering peripheral nervous system agonists or antagonists.

The knowledge of ANS pharmacology is particularly crucial in acute medical specialities, where precise control over the cardiovascular system, airway dynamics, and other physiological parameters is essential. Physicians rely on drugs that selectively target specific adrenergic or cholinergic receptors to achieve optimal hemodynamic stability and other vital parameters [2].

Furthermore, pharmacists, physicians, intensivists, and medical students benefit from a comprehensive understanding of ANS pharmacology. By grasping the complexities of autonomic receptor modulation, healthcare professionals can make informed decisions regarding drug selection, dosing, and potential adverse effects. This knowledge enhances patient safety and improves clinical outcomes across various medical disciplines.

#### **2. Pharmacology of the sympathetic nervous system**

The SANS, often referred to as the "fight or flight" system, prepares the body for physical exertion and stressful situations. The primary neurotransmitter in the SANS is norepinephrine (noradrenaline), which interacts with adrenergic receptors located throughout the body. These receptors are categorized into two main subtypes: α and β [1].

The α-adrenergic receptors are further divided into α-1 and α-2 subtypes. α-1 receptors are predominantly located in blood vessels, leading to vasoconstriction when activated. This effect increases systemic vascular resistance, elevating blood pressure. α-1 agonists such as phenylephrine find clinical utility in managing hypotension during anesthesia. Conversely, α-1 antagonists like prazosin induce vasodilation and alleviate conditions such as benign prostatic hyperplasia and hypertension. α-2 receptors are primarily located presynaptically in sympathetic nerve terminals, where their activation inhibits the release of norepinephrine, resulting in negative feedback regulation of sympathetic outflow. Clonidine, an α-2 agonist, is commonly used in anesthesia and surgery to attenuate sympathetic responses, promote sedation, and enhance perioperative analgesia [1].

β-adrenergic receptors consist of three subtypes: β-1, β-2, and β-3. β-1 receptors are predominantly found in the heart, activating heart rate and contractility [1]. β-1 agonists like dobutamine enhance cardiac output in patients with heart failure or cardiogenic shock. β-1 antagonists, such as metoprolol, are widely used in to mitigate the adverse effects of excessive sympathetic stimulation on the cardiovascular system [3]. β-2 receptors are abundant in the bronchial smooth muscle and peripheral vasculature, leading to bronchodilation and vasodilation when stimulated [1]. β-2 agonists like salbutamol are commonly utilized to manage asthma and chronic obstructive pulmonary disease (COPD) [3].

Conversely, β-2 antagonists may be used in conditions like glaucoma, where reduced intraocular pressure is desirable [3]. β-3 receptors are primarily present in adipose tissue, where their activation promotes lipolysis. While the therapeutic significance of β-3 receptors is still being explored, their modulation may hold potential in treating obesity and metabolic disorders.

#### **2.1 Sympathomimetics**

#### *2.1.1 α-1 receptor agonists*

α-1 receptors dominate most of the smooth muscle of the autonomic target organs. They mediate primarily arterial and venous vasoconstriction when

*Pharmacology of the Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.113006*

activated. Drugs that mimic the action of epinephrine and norepinephrine can be called sympathomimetics. These drugs can be divided into direct and indirect agonists [4].

Direct agonists interact with the adrenoreceptor directly and subsequently activate them, while indirect agonists depend on their ability to enhance the effect of endogenous catecholamines. The indirect agonist can do so by (i) displacing catecholamine from their adrenergic nerve endings and inducing their release (e.g., the mechanism of action of tyramine), (ii) inhibiting the clearance of catecholamines by decreasing their neuronal reuptake (e.g., the mechanism of action of cocaine and tricyclic antidepressants), or (iii) preventing the enzymatic metabolism of norepinephrine (monoamine oxidase and catechol-O-methyltransferase inhibitors) [4].

#### *2.1.1.1 Direct-acting* α*-agonists*

#### *2.1.1.1.1 Phenylephrine*

The chemical formula of phenylephrine is C9H13NO2. It is an α-1 adrenergic agonist that only affects β receptors at very high doses. As it is not a catechol derivative, it is not broken down by catechol-O-methyltransferase (COMT) and has a longer duration of action than catecholamines. It can cause an increase in blood pressure by venous and arteriolar vasoconstriction, and since it does not act on β receptors, there is no direct effect on cardiac muscle. The increase in blood pressure causes reflex bradycardia by stimulation of baroreceptors [5].

The intravenous (IV) phenylephrine hydrochloride increases blood pressure in adults with clinically significant hypotension resulting primarily from vasodilation in such settings as septic shock or anesthesia. Phenylephrine hydrochloride (HCL) is also used over-the-counter in ophthalmic formulations to promote mydriasis and conjunctival blood vessel vasoconstriction, intranasal administration as a treatment for uncomplicated nasal congestion, and as an over-the-counter additive to topical hemorrhoid medications [5].

The ophthalmic formulations of phenylephrine act for 3–8 hours, while intravenous solutions have a practical half-life of 5 minutes and an elimination half-life of 2.5 hours. The bioavailability orally is 38%, and ophthalmic solutions have clinically significant absorption, especially if the cornea is damaged. This drug is mainly metabolized by monoamine oxidase A, monoamine oxidase B, and sulfotransferase family 1A member 3 (SULT1A3). The primary metabolite it forms is the inactive meta-hydroxymandelic acid, followed by sulfate conjugates. It can also be metabolized to phenylephrine glucuronide. About 86% of the drug is recovered in urine; 16% of it is unmetabolized, and 57% of it is inactive meta-hydroxymendelic acid, and 8% is inactive sulfate conjugates [6].

The adverse effects of these drugs are nausea, vomiting, and confusion. Since phenylepinephrine increases the afterload more than the preload, the decreased cardiac output can also lead to severe bradycardia, exacerbating angina, heart failure, and pulmonary hypertension. Overdose can be treated by discontinuing the medication, chronotropic medications, and vasodilators [5].

There are no absolute contraindications for using this drug apart from hypersensitivity reactions such as anaphylaxis or less severe asthmatic episodes. Currently, no antidote is available to reverse this drug's effects. The treatment of hypertension and reflex bradycardia is discontinuing the administration of the drug [5].

#### *2.1.1.1.2 Midodrine*

Midodrine is a prodrug (medication that turns into active form once it enters the body). It is used to manage patients with orthostatic hypotension or hypotension secondary to other clinical conditions or drug therapies [7].

The chemical formula of this drug is C12H19ClN2O4. It is water-soluble and distributed as tablets for oral administration. Dosage forms are 2.5 mg, 5 mg, and 10 mg. Midodrine is almost completely absorbed after oral administration and undergoes enzymatic hydrolysis to form its pharmacologically active metabolite, de-glymidodrine. The drug should be stored in an airtight container [8].

The plasma levels of this prodrug peak at about half an hour and decline with a half-life of approximately 25 minutes. The peak concentration of the metabolites reaches about 1–2 hours, and their half-life is about 3–4 hours. The absolute bioavailability is 93% and is not affected by food. Midodrine deglycination to desglymidodrine appears in many tissues, and the liver metabolizes both compounds [9].

It does not act on cardiac β-adrenergic receptors and poorly diffuses across the blood-brain barrier. Increased embryo reabsorption is revealed in animal studies, as well as reduced fetal body weight and decreased fetal survival. There is no controlled data on human pregnancy. It is labeled US FDA Pregnancy category C, but the potential benefits may warrant the use in pregnant women, despite potential risks. No data is available for excretion in animal and human milk, but use should be avoided, and caution is recommended [8].

The contraindications to the drug are allergy to the drug, kidney disease, or, if one cannot urinate, pheochromocytoma (adrenal gland tumor), overactive thyroid, high blood pressure even while lying down, and liver disease. Taking this drug alongside other drugs that constrict the blood vessels can increase blood pressure. Common adverse effects (1–10%) of the drug are supine hypertension, paresthesia, headache, npiloerection, dysuria, nausea, dyspepsia, and vomiting [8].

The oral lethal dose (LD 50) is approximately 30–50 mg/kg in rats, 67.5 mg/kg in mice, and 125–160 mg/kg in dogs. Overdose symptoms could include hypertension, piloerection (goosebumps), a sensation of coldness, and urinary retention. The single doses associated with overdosage or potentially life-threatening symptoms in humans are unknown. Desglymidodrine is dialyzable [9].

#### *2.1.1.2 Indirect-acting α-agonists*

#### *2.1.1.2.1 Ephedrine*

Ephedrine is an α- and β-adrenergic agonist; however, it also causes the indirect release of norepinephrine from sympathetic neurons, inhibiting norepinephrine reuptake and displacing more norepinephrine from storage vesicles. Its use is indicated in treating hypotension under anesthesia, allergic conditions, bronchial asthma, and nasal congestion. Its chemical formula is C10H15NO [10].

Ephedrine can be administered through oral, nasal, and intravenous routes (tablet/capsule:8–25 mg, Solution—0.5%, IV: 10–15 mg/1 mL). Ephedrine increases blood pressure by stimulating heart rate and cardiac output and variably increasing peripheral resistance. Activation of β-adrenergic receptors in the lungs causes bronchodilation. By stimulating α-adrenergic receptors in bladder smooth muscle cells, ephedrine also increases the resistance to the outflow of urine. Compared to when ephedrine is

#### *Pharmacology of the Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.113006*

used to treat hypotension, using ephedrine for hypotension prophylaxis is associated with a higher risk of hypertension [10].

The bioavailability of ephedrine is 88%, and oral ephedrine reaches an average maximum concentration (Cmax) of 79.5 ng/mL, with a time-to-peak concentration (Tmax) of 1.81 hours [10].

Ephedrine is largely unmetabolized in the body and can be N-demethylated to norephedrine or demethylated and deaminized to benzoic acid conjugates and 1,2-hydroxypropyl benzene. The route of elimination is through the urine; about 60% is excreted as unmetabolized parent compound and 13% as benzoic acid conjugates and 1% as 1,2-dihydroxypropylbenzene. There is a large degree of inter-patient variability on the half-life of this drug, but orally, the plasma elimination half-life is approximately 6 hours [10].

Its use is contraindicated in people with cardiovascular disease, hypertension, hyperthyroidism, pheochromocytoma, and closed-angle glaucoma [11]. Large doses of ephedrine cause nervousness, insomnia, vertigo, headache, tachycardia, palpitation, and sweating. Some patients have nausea, vomiting, and anorexia. Painful urination may occur as a result of a vesical sphincter spasm. Urinary retention may develop in males with prostatism. Cardiac arrhythmias and precordial pain may occur following administration of ephedrine sulfate injection, USP [11].

The LD50 in mice after oral administration is 785 mg/kg, after intraperitoneal administration is 248 mg/kg, and after subcutaneous administration is 425 mg/kg. An overdose of ephedrine will present with rapidly increasing blood pressure. The overdose can be managed with blood pressure monitoring and possibly administering parenteral antihypertensives [10].

#### *2.1.1.2.2 Methamphetamine*

It is a sympathomimetic agent widely used to treat attention deficit hyperactivity disorder (ADHD) and exogenous obesity. Its chemical formula is C10H15N. Methamphetamine is a white solid odorless crystal. The recommended storage temperature is −20°C. This drug is a potent stimulant of the central nervous system, and it affects the neurochemical mechanisms responsible for regulating body temperature, heart rate, blood pressure, appetite, attention, mood, and responses associated with alertness or alarm conditions. The drug's acute effects closely resemble the psychological and physiological effects of an epinephrine-provoked flight-or-fight response; these responses include increased heart rate, vasoconstriction, increased blood pressure, hyperglycemia, and bronchodilation. It causes the elimination of fatigue, increased mental alertness, increased focus, and decreased appetite [12].

When methamphetamine enters the brain, it causes a cascade of norepinephrine, dopamine, and serotonin release. It acts as a dopaminergic and adrenergic reuptake inhibitor to a lesser extent, and in a higher concentration, it can act as a monoamine oxidase inhibitor [12].

Absorption of methamphetamine occurs in the gastrointestinal tract, with peak concentrations occurring at 3.13–6.3 hours after ingestion, and its effects may continue up to 24 hours in larger doses. When the drug is administered by inhalation, or intranasally, a high degree of absorption occurs. The drug has a high lipophilicity; it is distributed across the blood-brain barrier and crosses the placenta. This drug should be avoided in breastfeeding mothers as it is excreted through milk. The drug excretion occurs through the urine and increases with the acidic pH metabolization of methamphetamine occurs in the liver by aromatic hydroxylation, N-dealkylation, and deamination; at least seven metabolites have been identified in urine [12, 13].

The concurrent use of monoamine oxidase inhibitors with methamphetamine is contraindicated as a hypertensive crisis may occur. It is also contraindicated in patients with glaucoma, advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity, or idiosyncrasy to sympathomimetic amines. It is a Pregnancy category C drug*.* It is shown to have teratogenic and embryocidal effects in mammals given multiple high human doses. There are no adequate and well-controlled studies in pregnant women, but it is recommended not to be used during pregnancy unless the potential benefit justifies the potential risk to the fetus [14].

Acute overdose of methamphetamine is manifested by restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia, and rhabdomyolysis. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning usually terminates in convulsions and coma [12].

Therapeutic methamphetamine blood concentration is 20–60 ug/dL; toxic methamphetamine blood concentration is 60–500 ug/dL, and lethal methamphetamine blood concentration is 1–4 mg/dL [12]. Benzodiazepines represent first-line treatment for methamphetamine toxicity but frequently require repeated and escalated dosing to achieve the effect [15].

#### *2.1.2 α-2 receptor agonists*

The α-2 receptors constitute a family of G-protein-coupled receptors (GPCRs) with three pharmacological subtypes, α-2A, α-2B, and α-2C [16]. Most α-2A and α-2C subtypes are located mainly in the presynaptic central nervous system. When stimulated, these receptor subtypes may be responsible for sedative, analgesic, and sympatholytic effects. On vascular smooth muscle, α-2B receptors are more prevalent and have been shown to mediate vasopressor effects. All three subtypes have been shown to inhibit adenylyl cyclase, resulting in decreased levels of cyclic adenosine monophosphate and hyperpolarization of noradrenergic neurons in the medial dorsal pons, specifically in the locus ceruleus [16]. As cyclic adenosine monophosphate is inhibited, potassium efflux via calcium-activated channels prevents calcium ions from entering the nerve terminal, inhibiting neural discharge. This process inhibits the release of norepinephrine and reduces the activity of ascending noradrenergic pathways, resulting in hypnosis and sedation. Activation of this negative feedback loop may also result in decreased heart rate and blood pressure, as well as a diminished sympathetic stress response. Stimulation of α-2 receptors in the spinal column's dorsal horn inhibits nociceptive neurons and reduces substance P release. Although there is evidence for supraspinal and peripheral sites of action, it is believed that the spinal mechanism accounts for the majority of the analgesic effects of α-2 agonist drugs [16].

Guanabenz, guanfacine, clonidine, tizanidine, medetomidine, and dexmedetomidine are all α-2 agonists with different potencies and affinities for different α-2 receptor subtypes. Clonidine, tizanidine, and dexmedetomidine have seen the most clinical use and will be discussed in greater depth.

#### *2.1.2.1 Clonidine*

Clonidine, an imidazole molecule, is a selective partial agonist for α-2 adrenoceptors with a 200:1 ratio (α2–α1).

*Pharmacology of the Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.113006*

Clonidine stimulates the brain stem's α-adrenoreceptors. This action diminishes central nervous system sympathetic outflow and decreases peripheral resistance, renal vascular resistance, heart rate, and blood pressure.

Clonidine can be administered *via* various routes: oral, intravenous, transdermal, rectal, and different neuraxial routes. It is rapidly and nearly completely absorbed following the oral route, reaching peak plasma levels in 60–90 minutes. A time-release transdermal patch can also administer clonidine; however, therapeutic levels require at least 2 days. It has an elimination half-life of 8–12 hours, with 50% of the drug metabolized in the liver to inactive metabolites and the rest being excreted unaltered in the kidney [17].

#### *2.1.2.2 Clinical uses*

Clonidine and guanfacine may be used to treat children and adolescents with attention deficit hyperactivity disorder. The reduced firing of presynaptic neurons releasing norepinephrine into the prefrontal cortex decreases the impulsive and hyperactive behavior seen in ADHD. Because of their additive effects on serotonin and γ-aminobutyric acid receptors, α-2 agonists are the most commonly utilized drugs to treat lack of sleep in children with ADHD. Clonidine also treats chronic pain disorders and withdrawal from opiates, benzodiazepines, alcohol, cocaine, food, and cigarette smoke [17].

Clonidine as an adjuvant has several advantages, including a reduction in the amount of opioids necessary for analgesia and hence a likely reduction in opioidrelated side effects, titrated sedation and anxiolysis with no additive respiratory depression when combined with opioids and vasodilation and enhanced circulation of the cerebral, coronary, and visceral vascular beds [17].

Clonidine has lately been utilized as a premedication in individuals with considerable pretreatment anxiety. It has been found to improve mask application during anesthesia induction and to reduce anesthetic requirements by 40–60% in the pediatric population.

#### *2.1.2.3 Dexmedetomidine*

Dexmedetomidine, as clonidine, is a highly selective α-2 agonist with a higher affinity for the α-2 receptor (**Figure 1**). Clonidine has a specificity of 220: 1 (α-2: α-1), while dexmedetomidine has a specificity of 1620: 1. It is a full agonist of α-2 adrenergic receptors and the pharmacologically active d-isomer of medetomidine [18].

Dexmedetomidine induces a state of unconsciousness equivalent to normal sleep by activating central pre- and postsynaptic α-2 receptors in the locus ceruleus, with the added benefit of patients remaining easily stimulated and cooperative.

Dexmedetomidine generates a dose-dependent biphasic blood pressure response. Low-dose intravenous infusion lowers mean arterial pressure due to selectivity for central and peripheral α-2 receptors. The subsequent decreases in heart rate and systemic vascular resistance indirectly diminish cardiac output and systolic blood pressure. These actions help modulate the stress response, improve stability, and guard against drastic changes in cardiovascular parameters after surgery [18].

Dexmedetomidine can be given orally, intravenously, intramuscularly, buccally, and intranasally. It has a two-compartment distribution and elimination model. It has a (T1/2 β) of 2 hours for elimination. However, it is a highly lipophilic medication that rapidly dispersed and redistributed, with a (T1/2 α) of only 6 minutes for distribution. This has a

**Figure 1.** *Dexmedetomidine molecule.*

rapid onset but only a short duration of clinical action. Because of its fast redistribution and removal, it is a suitable agent for infusion procedures. Dexmedetomidine is metabolized *via* direct glucuronidation and CYP2A6. Approximately 80–90% is eliminated in the urine, with the remaining 5–13% detected in the feces [18].

Pharmacokinetic interactions are unusual in most cases. However, dosage adjustments for concurrently administered sedatives may be required due to drug potentiation. Adding an α-2 agonist to a sedative regimen reduces the need for opioids by 50–75% and benzodiazepines by up to 80%. Dexmedetomidine's context-sensitive half-life ranges from 4 minutes after a 10-minute infusion to 250 minutes after an 8-hour infusion [18].

#### *2.1.2.4 Clinical uses*

Dexmedetomidine has three primary therapeutic applications: (a) in-hospital prolonged sedation, (b) procedure sedation and general anesthesia, and (c) obtunding emerging delirium. It is utilized as a sedative drug in critical care settings for critically ill patients who require prolonged sedation and mechanical ventilation. Dexmedetomidine possesses all of the features of an ideal critical care sedative. It does not cause respiratory depression, is analgesic and anxiolytic, has a fast onset, is titratable, and promotes drowsiness while maintaining hemodynamic stability. Finally, dexmedetomidine is exceptionally effective in treating the emerging delirium that can occur after general anesthesia, particularly in children. It has a significant relaxing effect without causing respiratory depression. This is a significant benefit over other medications typically used in such situations and requires additional study.

#### *2.1.3 β-1 agonists*

#### *2.1.3.1 Dobutamine*

Dobutamine is a synthetic sympathomimetic drug that selectively stimulates β-1 adrenergic receptors. It mimics the action of endogenous catecholamines like epinephrine but has a more specific effect on β-1 receptors. Dobutamine is typically available as a solution for intravenous infusion. The healthcare provider determines the concentration and dosage regimen based on the individual's specific needs.

Pharmacokinetically, dobutamine is administered intravenously due to its poor oral bioavailability. It has a rapid onset of action and a short duration of action. The drug is metabolized in the liver and excreted primarily in the urine.

#### *Pharmacology of the Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.113006*

Dobutamine acts primarily as a β-1 adrenergic receptor agonist. It increases the contractility of the heart muscle (positive inotropic effect) and enhances cardiac output. It also leads to mild vasodilation, primarily affecting the arterial system. In the clinical settings, dobutamine primarily treats acute heart failure or cardiogenic shock. It is used to improve cardiac contractility and increase cardiac output in these conditions.

#### *2.1.3.2 Dopamine*

Dopamine is a neurotransmitter and a sympathomimetic drug that acts on dopamine receptors in the central and peripheral nervous systems. It is crucial in physiological processes, including movement, motivation, reward, and blood pressure regulation. Dopamine is typically available as a solution for intravenous infusion. The healthcare provider determines the concentration and dosage regimen based on the individual's specific needs.

Pharmacokinetically, dopamine is administered intravenously due to its poor oral bioavailability. It has a rapid onset of action and a short duration of action. The drug is rapidly metabolized in the liver and excreted in the urine.

Dopamine acts on different receptors, including dopamine receptors, α-1 adrenergic receptors, and β-adrenergic receptors. Its effects vary depending on the dose administered. Dopamine primarily stimulates dopamine receptors at low doses, leading to renal and mesenteric vasodilation. It activates higher doses of α-1 and β-1 adrenergic receptors, increasing cardiac contractility and vasoconstriction.

Dopamine treats various conditions, including hypotension, shock, and low cardiac output states. It helps increase blood pressure and cardiac output by improving cardiac contractility and causing peripheral vasoconstriction.

#### *2.1.3.3 Epinephrine (adrenaline)*

Epinephrine, also known as adrenaline, is a naturally occurring catecholamine and a potent nonselective adrenergic agonist. It acts on α- and β-adrenergic receptors, producing various physiological effects. Epinephrine is available in different formulations, including solutions for intravenous injection, autoinjectors, and inhalers. The concentration and specific formulation may vary depending on the intended use.

Epinephrine can be administered *via* various routes, including intravenous, intramuscular, subcutaneous, and inhalation. It has a rapid onset of action and a short duration of action. The drug is metabolized in the liver and other tissues, and the metabolites are excreted in the urine. Epinephrine acts on both α- and β-adrenergic receptors. It produces various effects, including increased heart rate and contractility, bronchodilation, peripheral vasoconstriction, and increased blood pressure. These effects are beneficial in emergencies such as anaphylaxis, cardiac arrest, and severe asthma exacerbations.

Epinephrine is used in various emergencies, including anaphylaxis (severe allergic reactions), cardiac arrest, bronchospasm, and severe asthma exacerbations. It also restores blood pressure and maintains organ perfusion during resuscitation efforts.

#### *2.1.4 β-2 agonists*

β-adrenergic receptor agonists have long been used to treat both acute asthma symptoms and the prevention of exercise-induced asthma in adults and children

and to treat COPD. They mimic the actions of catecholamines such as epinephrine, norepinephrine, and dopamine in triggering various autonomic responses within the body. β-2 agonists significantly affect the smooth muscle of the airway, uterus, gut, and systemic vasculature.

As part of our functional autonomic system, circulating catecholamines stimulate adrenergic receptors, resulting in parasympathetic and sympathetic physiological reactions. β-2 agonists operate as ligands to adrenergic receptors with higher selectivity for β-2 adrenergic receptors, mimicking catecholamines. When the β-2 adrenergic receptor is activated, a transmembrane signal cascade is initiated that includes the heterotrimeric G protein, Gs, and the effector, adenylyl cyclase. Adenylyl cyclase then raises intracellular cAMP through ATP hydrolysis. The increased cAMP concentration activates the cAMP-dependent protein kinase A (PKA). PKA can phosphorylate intracellular substrates, which modulate various actions within the cell. PKA, in particular, operates in airway smooth muscle to phosphorylate Gq-coupled receptors, resulting in a cascade of intracellular signals that have been postulated to diminish intracellular Ca2+ or decrease Ca2+ sensitivity [19].

The increase in Ca2+ inhibits myosin light chain phosphorylation, which prevents airway smooth muscle contraction. This is the underlying mechanism of β-2 agonists, which boost bronchodilatory effects and are used to treat a variety of common respiratory disorders. There have been suggestions that β-2 agonists have antiinflammatory effects within the airway smooth muscle by decreasing intercellular adhesion molecule-1, decreasing granulocyte-macrophage colony-stimulating factor release, and stabilizing mast cell degranulation by inhibiting multiple inflammatory pathways.T16 The duration and start of the action of β-2 agonists influence their classification. The three categories are short-acting, long-acting, and, most recently, ultra-long-acting β-agonists.

#### *2.1.4.1 Short-acting β-2 agonists*

They are first-line drugs for treating acute asthma symptoms and exacerbations. They are also often used in treating COPD in conjunction with long-acting, inhaled corticosteroids or long-acting muscarinic agonists. These drugs are often administered through inhalation, either metered dosage, dry powder inhalation, or nebulization. Compared to alternative oral delivery, inhalation has a higher therapeutic benefit and fewer systemic side effects. This family includes Salbutamol (albuterol), Terbutaline, Levalbuterol, and Pirbuterol.

#### *2.1.4.2 Salbutamol*

Salbutamol absorption is highly dependent on both formulation and dosage as well as the way of delivery. A thorough description of the effect of delivery systems on salbutamol pharmacokinetics may occupy many book chapters and is beyond the scope of this piece; however, we will consider some of the key points. Salbutamol is usually administered *via* a compressed metered-dose inhaler with an immense buffer. This very efficient delivery mechanism assures good distribution, especially to smallto moderate-sized airways. It can, however, be inhaled using a dry powder inhaler, or nebulizer, orally or intravenously.

Salbutamol, a partial agonist, has the greatest bronchodilating action at low dosages. It binds to β2-adrenoceptors located on airway smooth muscle (ASM)

#### *Pharmacology of the Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.113006*

throughout the airways. This binding causes a postsynaptic action on adenyl cyclase, resulting in the formation of intracellular cyclic AMP (cAMP) from ATP, which in turn stimulates other effector molecules, including cAMP-dependent protein kinase A (PKA) and nucleotide exchange factor, which work together to cause intracellular Ca2+ sequestration, resulting in ASM relaxation. Despite that salbutamol's primary function is bronchodilation, it also suppresses mast cell mediator release and tumor necrosis factor α (TNF) release from monocytes. It also enhances mucus production and clearance of the mucociliary tract. It has extensive effects across numerous organ systems as a sympathomimetic, and it causes dose-dependent tachycardia, hyperglycemia, hypokalemia, and tremor. The systemic metabolic effects inducing glycogen breakdown and concomitant insulin release (possibly stimulated by pancreatic β2 cells) combine to cause high blood sugar levels and serum hypokalemia, with the former occurring as a consequence of cellular sodium excretion and potassium influx (Na-K-ATPase pump).

This side effect is beneficial in the emergency treatment of hyperkalemia, where ongoing salbutamol administration can decrease serum potassium between 1 and 1.5 mmol/L. However, it can also have complications such as dose-related tremors (the salbutamol shakes'), and when combined with cardiac receptor stimulation, stimulation can lead to tachyarrhythmias. Tachyphylaxis to β-2 agonists arises as soon as 1 week after starting regular medication and is more apparent with β 2-agonist monotherapy.

#### *2.1.4.3 Terbutaline*

It is also a selective β-2 adrenoceptor agonist used to prevent and reverse bronchoconstriction. Approximately, its volume of distribution is about 1.6 L/kg. After 72 hours, an oral dose of terbutaline gets eliminated in the urine by 40%. Terbutaline sulfate conjugated was the most predominant metabolite in the urine. Terbutaline parenteral levels are 90% removed in the urine, with roughly 2/3 as the unaltered primary substance. In the feces, less than 1% of a terbutaline dose gets eliminated.

#### *2.1.4.4 Long-acting β-2 agonist*

They are commonly used in managing asthma and COPD patients, often combined with inhaled corticosteroids. There is evidence that combination therapy is more effective than monotherapy. They have a longer onset time than short-acting medications, with salmeterol having an onset period of up to 15 minutes and lasting at least 12 hours. The suggested route of administration is inhalation, as with short acting. They are typically used as a second-line treatment in asthma patients who have failed to get clinical relief with short-acting medications. Salmeterol and formoterol are the commonest drugs in this group.

#### *2.1.4.5 Salmeterol*

In asthmatic patients, a 50 μg dose of inhaled salmeterol powder reaches a Cmax of 47.897 pg./mL, with a Tmax of 0.240 h and an AUC of 156.041 pg./mL/h. The distribution volume of the main compartment is 177 L, and the distribution volume of the peripheral one is 3160 L. Salmeterol is 96% protein linked to albumin and α-1-acid glycoprotein in plasma. It is primarily processed by CYP3A4 to α-hydroxysalmeterol1, with little contribution from an unknown process to an O-dealkylated metabolite.

Salmeterol is removed in the feces at 57.4% and the urine at 23%. Only around 5% of the dosage is excreted in the urine as unaltered salmeterol.

#### *2.1.4.6 Formoterol*

It has a fast onset of action (about 2–3 minutes) and an extended duration of action (up to 12 hours). In asthmatic patients, long-acting β-agonists such as formoterol without accompanying inhaled corticosteroids should be avoided, as long-acting monotherapy has been linked to an increased risk of asthma-related fatalities. Its pulmonary bioavailability is estimated to be around 43% of the delivered dose, whereas total bioavailability in the body is approximately 60% of the supplied dose (since systemic bioavailability comprises absorption in the stomach). Following inhalation, formoterol is rapidly absorbed into the plasma. Formoterol Tmax in healthy adults ranged from 0.167 to 0.5 hours. Cmax and AUC were 22 pmol/L and 81 pmol.h/L after a single dosage of 10 mcg, respectively. Tmax in asthmatic adults ranged from 0.58 to 1.97 hours. Cmax and AUC0–12h after a single dose of 10mcg were 22 pmol/L and 125 pmol.h/L, respectively; after several doses of 10 mcg, Cmax and AUC0-12 h were 41 pmol/L and 226 pmol.h/L, correspondingly. Across normal dosing ranges, absorption appears to be dose proportionate. It is 34–38% binding to plasma protein. It is predominantly processed by direct glucuronidation of the primary drug and O-demethylation of the primary drug, followed by glucuronidation. Minor mechanisms include primary drug sulfate conjugation and primary drug deformylation followed by sulfate conjugation, albeit these minor pathways have not been completely studied.

#### *2.1.4.7 Ultra-long-acting β-2 agonist*

Ultra-long-acting medications provide the longest duration of action, up to 24 hours, with the added benefit of being a once-a-day therapeutic dosage. The FDA has approved Indacaterol as a maintenance medication for COPD patients in combination with other bronchodilators. Indacaterol can be taken as a dry powder with a 5-minute onset of action. Many different ultra-LABAs are now being researched, with the potential to increase compliance and efficiency over current asthma and COPD therapy choices. Indacaterol, Vilanterol, and Oladaerol are the drugs in this group.

#### *2.1.4.8 Administration*

Metered-dose inhalers, nebulizers, dry powder inhalers, orally, subcutaneously, or intravenously are the most common delivery methods for β-2 agonists. Inhalation is the primary mode of delivery for β-2 agonists in treating asthma and COPD. Inhalation concentrates the therapeutic impact of the medicine on the airway's smooth muscles while minimizing the drug's diffusion to the systemic circulation. There is no association between the therapeutic impact of inhaled β-2 agonists and their peak plasma levels. Oral β-2 agonists, which have been demonstrated to exacerbate systemic side effects, are used less commonly. Terbutaline can also be administered intravenously, intramuscularly, or orally.

#### *2.1.4.9 Adverse effects*

The most prevalent side effect of β-2 agonists is desensitizing the β-2 adrenergic receptor to the β-2 agonist. Because adrenergic receptors have comparable features, β-2 *Pharmacology of the Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.113006*

agonists can have an "off-target" effect by stimulating α-1, α-2, or β-1 receptors. β-2 agonists' most prevalent adverse effects include the cardiovascular, metabolic, or musculoskeletal systems. Because of the vasodilatory impact on peripheral vasculature and a concomitant decrease in cardiac venous return, mechanisms of compensation show as tachycardia is relatively prevalent, particularly in the first few weeks of treatment. According to several publications ranging from single case reports to case-control studies, cardiac toxicity in the form of arrhythmias, cardiomyopathy, and ischemia has been more strongly associated with earlier-generation β-2 agonists. β-2 agonists have been demonstrated to lower serum potassium levels by causing an inward influx of potassium into cells *via* an action on the membrane-bound Na/K-ATPase, which can lead to hypokalemia. β-2 agonists also accelerate glycogenolysis, which might result in unintentional increases in serum glucose. Musculoskeletal tremors are another possible side effect, which is more familiar with using oral β-2 agonists. The severity of these side effects is often related to factors such as the affinity of each β-2 agonist to its specific receptor and medication dosages. Several studies additionally discovered hypoxemia and hypercapnia to be aggravating variables for β-2 agonist cardiotoxicity.T25

#### **2.2 Sympatholytics**

#### *2.2.1 α-blockers*

*Sympatholytic drugs* inhibit the effects of catecholamines by acting on postsynaptic adrenergic receptors present in target organs or by inhibiting the synthesis and storage of the catecholamines. These drugs can be divided into two subtypes, selective and nonselective α-receptor blockers.

*Nonselective α-receptor antagonists* block both the α-1 receptors as well as α-2 receptors. Blocking α-1 receptor causes vasodilation, while α-2 receptor blockade will reduce the force of vasodilation due to increased release of Norepinephrine. These medications, such as pheochromocytoma, are widely used in patients with increased sympathetic activity.

*Selective α-1 receptor blockers* act on the receptors and cause vasodilation; therefore, they are widely used in patients with hypertension and cause smooth muscle relaxation, so they help manage benign prostate hyperplasia [20].

The mechanism of action of *α-2 receptor blockers* is not known, although, in principle, they are known to inhibit negative feedback of norepinephrine release by stimulating the norepinephrine system, and they inhibit the effects of norepinephrine on postsynaptic α-2 adrenoceptors [20, 21].

#### *2.2.1.1 Nonselective α-receptor blockers*

#### *2.2.1.1.1 Phentolamine*

It is a nonselective α-receptor blocker used mainly to diagnose pheochromocytoma and to control or prevent paroxysmal hypertension immediately before or during pheochromocytoma ectomy. It is used to reverse soft tissue anesthesia, such as the tongue and the lips, and the associated functional deficits resulting from an intraoral submucosal injection of a local anesthetic containing a vasoconstrictor.

The drug is available in injection forms from 0.235 mg/1 mL to 10 mg/1/mL. The chemical formula of the drug is C17H19N3O. α-receptors are present in blood vessels;

when they are activated by phentolamine, the blood vessels widen as the muscles relax and therefore decrease blood pressure. This drug maintains long-acting chemical sympathectomy. Phentolamine also stimulates β-adrenergic receptors and therefore causes a positive inotropic and chronotropic effect on the heart and increases cardiac output.

Phentolamine is only about 20% as active after oral administration as after parenteral administration. About 10–13% of the drug is eliminated unchanged in the urine, while the fate of the rest of the drug is unknown. The Tmax is 30–60 minutes. After intravenous administration of the drug, the elimination half-life is 19 minutes; after oral administration, it is 5–7 hours.

Some common adverse effects of the drug are weakness, dizziness, flushing, orthostatic hypotension, and nasal congestion, which have been reported in patients receiving phentolamine. Adverse GI effects are common and include abdominal pain, nausea, vomiting, diarrhea, and exacerbation of peptic ulcer. Adverse cardiovascular effects include prolonged hypotension, tachycardia, cardiac arrhythmias, and angina, especially after parenteral administration. Myocardial infarction and cerebrovascular spasm or occlusion, usually associated with marked hypotension and a shock-like state, have been reported occasionally following parenteral administration of phentolamine. Deaths have occurred after IV administration of phentolamine for the diagnosis of pheochromocytoma.

No specific antidote is available for phentolamine toxicity; however, in shock-like conditions such as a dangerous decrease in blood pressure or other evidence of shock, the person should be treated promptly with supportive care, and IV norepinephrine infusion can be administered if necessary. Epinephrine should not be used as it can cause a paradoxical decrease in blood pressure [22].

The oral LD50's (mg/kg) in mice is 1000, and in rats, it is 1250. No teratogenic or embryotoxic effects were observed in the rat, mouse, or rabbit studies, and no adequate and well-controlled studies in pregnant women are available. If the potential benefit of phentolamine justifies the potential risk to the fetus, the drug can be used. Whether or not the drug is excreted in human milk is unknown. As many drugs are excreted through human milk and since there is potential for adverse reactions in nursing infants, a decision should be made whether or not to continue the drug, considering the importance of the drug to the mother [22].

#### *2.2.1.2 Selective α-receptor blockers*

#### *2.2.1.2.1 Prazosin*

Prazosin is an α-1 receptor blocker used to treat hypertension, and recently, many studies have evaluated the drug's benefits in controlling post-traumatic stress disorder symptoms and associated nightmares. Other members of this drug class include Doxazosin, Terazosin, Tamsulosin, and Alfuzosin. This effect likely occurs through the inhibition of adrenergic stimulation found in states of hyperarousal. As this agent does not negatively impact lung function, it can manage hypertension in chronic obstructive lung diseases [23].

The chemical formula of the drug is C19H21N5O4. The usual adult for hypertension is 1 mg orally 2 or 3 times a day, initially, and the maintenance dose is 1–20 mg orally per day in divided doses [24]. It can be used alone or alongside other blood pressurelowering agents, including diuretics and β-adrenergic blocking agents. The decrease in blood pressure may occur in both standing and supine positions [23].

*Pharmacology of the Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.113006*

After administering the oral dose, the peak plasma level of the drug is reached by approximately 3 hours, and the half-life is about 2–3 hours. Prazosin is metabolized in the liver by demethylation and conjugation and is excreted mainly in the bile and feces. The clearance of the drug is decreased in people with congestive heart failure.

As the drug lowers blood pressure, it can cause a clinically significant decrease in cardiac output, heart rate, blood flow to the kidney, and glomerular filtration rate. The decrease in blood pressure may occur in both standing and supine positions [23]. Shock caused by low blood pressure should first be treated with volume expanders, and vasopressors should be used if deemed necessary. Renal function should be monitored and supported as needed [25].

The LD50 in humans is 285 μg/kg orally. Severe drowsiness and decreased reflex occurred with ingesting at least 50 mg of Prazosin. There was no fall in blood pressure, and the child recovered without complications. The drug is classified as a Pregnancy category C drug. There are no adequate studies for determining the drug's safety during pregnancy. Specific cases of emergent use for blood pressure control during pregnancy showed no effects on the fetus or neonate. As the drug is excreted in small amounts in breast milk, it should be used cautiously in breastfeeding mothers.

Avoid alcohol and licorice with the use of this drug. Its absorption is not affected by food. Acute symptomatic liver injury due to prazosin is rare, and severe hepatotoxicity must be rare if it occurs at all [26].

#### *2.2.1.2.2 Tamsulosin*

It is an α-1A and α-1B adrenergic receptor antagonist used to treat benign prostatic hyperplasia, ureteral stones, female voiding problems, and prostatitis. The chemical formula is C20H28N2O5S(R38). It is available in the form of tablets, and the dose for treatment of adult benign prostate hyperplasia is 0.4 mg orally once a day; the dose may be increased to 0.8 mg orally once a day in patients who fail to respond to 0.4 mg once a day within 2–4 weeks [27].

The most significant effect of this drug is in the bladder and prostate, where the α-1A and α-1B adrenergic receptors are most common. The drug's action leads to the relaxation of prostate and bladder muscles, allowing for better urinary flow. Tamsulosin binds to α-1A receptors 3.9–38 times more selectively than α-1B and 3–20 times more selectively than α-1D. A significant effect on urinary flow with a reduced incidence of adverse reactions like orthostatic hypotension is allowed through this selectivity [28].

Tamsulosin is absorbed 90% in patients who are fasting. Taking the drug with food increases the time to maximum concentration from 4 to 5 hours to 6–7 hours but increases bioavailability by 30% and maximum plasma concentration by 40–70% [28].

The drug is metabolized by cytochrome P450 (CYP) 3A4 and 2D6 in the liver, with some metabolism by other CYPs. There is a low rise in liver transaminases by tamsulosin, but clinically, apparent liver injury is rare [28].

The oral LD50 in rats is 650 mg/kg. In an overdose, the patients might have hypotension that should be managed supportively by lying supine, administering fluids, or if further progression occurs, vasopressors might be needed, and renal function should be closely monitored. As tamsulosin is highly protein-bound, dialysis does not assist in treating overdose [28].

Animal studies have not shown any fetal harm caused by tamsulosin, but this drug is not indicated for use in women. Tamsulosin is excreted in the milk of rats, but no studies have been conducted about the effects of exposure to it. Male and female rats have been shown to have fertility affected by impairment of ejaculation and fertilization. In men, ejaculation problems have been recorded with the use of tamsulosin. At levels above the recommended dose, tamsulosin may be carcinogenic. There is a slight increase in mammary gland fibroadenomas and adenocarcinoma rates in female rats [28].

#### *2.2.2 β-blockers*

β-blockers block the physiological impacts of sympathetic nerve stimulation or circulating catecholamines on β-adrenoceptors, which exist across different organs in the body. Many organs have both β1 and β2 receptors coexisting (**Table 1**). For example, approximately 80% of the receptors are of the β-1 subtype in a typical individual heart. In heart failure, β1 receptors are downregulated, allowing a greater number of β2 receptors to be detected. The physiological and therapeutic effects of a β-blocker are determined by the actual quantity of β-1 or β-2 receptors in the various organs, the β-blocker's affinity, and the local drug concentration. When the bioavailability of β-blockers with a strong affinity for β-adrenoceptors is not too low, they can be helpful in small doses. Their effect persists even if they are washed out of the extracellular area. As a result, the plasma half-life of the β-phase of elimination cannot forecast their duration of activity. This is particularly true for many medicines that have a high affinity and a short plasma half-life (2–4 h for the β-phase).T26

Many β-blockers have additional features that may influence their value in individuals:


1.*Selectivity*: Considering β-blockers' desired effects are achieved by blocking β1-receptors, which dominate on the heart, "cardioselective" drugs with greater

#### **Table 1.**

*Presence of β1–β2 receptors in various organ.*

*Pharmacology of the Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.113006*


#### **Table 2.** *Selectivity of β-blockers.*

sensitivity for this receptor are often recommended. However, "cardioselectivity" is not 100% and diminishes with increasing doses. Atenolol, bisoprolol, and metoprolol are examples of "cardioselective" β-blockers (**Table 2**).


The extent to which β-blockers are eliminated by the kidney or the liver varies, usually with considerable first-pass metabolism. Lipid-soluble β-blockers, such as labetalol, metoprolol, pindolol, and propranolol, are typically eliminated *via* the liver, whereas water-soluble β-blockers, such as atenolol, get eliminated by the kidney. The bioavailability of drugs removed by the liver varies significantly between populations. Most β-blockers have a short half-life; those removed through the kidney have a prolonged half-life.

#### *2.2.2.1 Side effects*

β-blockers have multiple unwarranted side effects secondary to their mechanism and site of actions, mainly:


#### **3. Pharmacology of the parasympathetic nervous system (PANS)**

The PANS, often called the "rest and digest" system, conserves energy and promotes homeostasis during periods of relaxation. Acetylcholine is the primary neurotransmitter in PANS signaling, acting on cholinergic receptors in various tissues. Cholinergic receptors are divided into two major types: nicotinic and muscarinic cholinergic receptors [1].

Nicotinic receptors are found at the neuromuscular junction and in the SANS and PANS ganglia. Activation of these receptors leads to subsequent muscle contraction or neurotransmitter release [1]. Nicotinic agonists, such as nicotine, are used primarily in smoking cessation therapies due to their stimulatory effects on the central nervous system [3]. In contrast, neuromuscular blocking agents, which act as nicotinic antagonists, are utilized in anesthesia to induce muscle relaxation during surgical procedures.

Muscarinic receptors: Muscarinic receptors are further classified into five subtypes, M1–M5. The PANS innervates these receptors in various target tissues, including the heart, smooth muscles, exocrine glands, and CNS structures. M1 receptors are predominantly located in the CNS, where their activation modulates cognitive function and memory. M2 receptors are primarily found in the heart, where activation slows heart rate and reduces contractility. M3 receptors are abundant in smooth muscles, glands, and endothelial cells. Stimulation of M3 receptors leads to bronchoconstriction, increased glandular secretions, and vasodilation.

The clinical utility of muscarinic agonists is limited compared to their antagonists. However, muscarinic antagonists, also known as anticholinergic drugs, play a crucial role in anesthesia. These agents, such as atropine and glycopyrrolate, counteract excessive PANS activity during anesthesia induction; prevent unwanted bradycardia, reduce salivary, and bronchial secretions; and facilitate intubation [1].

#### **3.1 Parasympathomimetics**

#### *3.1.1 Muscarinic receptor agonist*

#### *3.1.1.1 Pilocarpine*

Pilocarpine is a parasympathomimetic drug classified as a muscarinic receptor agonist. It is derived from the Pilocarpus plant and primarily acts on muscarinic

#### *Pharmacology of the Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.113006*

receptors to produce pharmacological effects similar to acetylcholine. Pilocarpine is available in various formulations, including eye drops, tablets, and solutions. Eye drops are commonly used for ophthalmic purposes. Concentrations may vary depending on the specific indication. Storage conditions may involve protecting the drug from light and excessive heat.

Pilocarpine can be administered topically to the eye or orally. When applied topically to the eye, it has poor systemic absorption. Oral pilocarpine is well-absorbed from the gastrointestinal tract. The drug undergoes hepatic metabolism, primarily *via* hydrolysis, and is excreted mainly in the urine.

Pilocarpine selectively activates muscarinic receptors, predominantly the M3 subtype. It stimulates cholinergic receptors in various tissues, leading to miosis (pupillary constriction), increased salivation, sweating, bronchoconstriction, and gastrointestinal motility.

Clinically, pilocarpine eye drops are commonly used to treat glaucoma, where they reduce intraocular pressure by increasing the drainage of aqueous humor from the eye. Pilocarpine can also manage dry mouth (xerostomia) associated with Sjögren's syndrome or radiation therapy.

Pilocarpine is contraindicated in individuals with a known hypersensitivity to the drug, uncontrolled asthma, acute iritis, or narrow-angle glaucoma. It should be used cautiously in patients with cardiovascular diseases or gastrointestinal disorders. Other common side effects of pilocarpine may include localized ocular effects like temporary blurred vision, eye discomfort, or burning sensation when used as eye drops. Systemic effects can include increased sweating, increased salivation, gastrointestinal disturbances (such as nausea, vomiting, or diarrhea), and bronchoconstriction.

In cases of overdose or excessive use, pilocarpine can lead to excessive cholinergic stimulation. Symptoms may include profuse sweating, salivation, miosis, gastrointestinal distress, and potentially life-threatening cardiovascular effects. Treatment may involve discontinuing the drug, supportive measures, and administering atropine as a competitive antagonist to counteract the excessive muscarinic effects.

#### *3.1.2 Acetyl-cholinesterase inhibitors*

#### *3.1.2.1 Neostigmine*

Neostigmine is a reversible acetylcholinesterase inhibitor, classified as a parasympathomimetic drug. It increases the concentration of acetylcholine at cholinergic synapses by inhibiting the enzyme acetylcholinesterase, which breaks down acetylcholine. Neostigmine is available in various forms, including oral tablets and solutions for injection. The concentration and specific formulation may vary depending on the intended use.

Neostigmine can be administered orally, intramuscularly, or intravenously. It has poor oral bioavailability and is rapidly metabolized by esterases in the plasma and tissues. The elimination half-life is relatively short.

Neostigmine inhibits acetylcholinesterase, accumulating acetylcholine and exerting its effects at cholinergic synapses. It enhances neuromuscular transmission, leading to increased muscle strength and tone. It also affects cholinergic neurotransmission in other systems, such as the gastrointestinal tract.

Neostigmine is primarily used to manage myasthenia gravis, a neuromuscular disorder characterized by muscle weakness. It is also employed to reverse the effects of non-depolarizing neuromuscular blocking agents after surgery and to treat urinary retention.

Neostigmine is contraindicated in individuals with known hypersensitivity to the drug or those with mechanical gastrointestinal or urinary tract obstruction. It should be used cautiously in patients with asthma, epilepsy, or bradycardia. Other common side effects of neostigmine include gastrointestinal disturbances such as nausea, vomiting, diarrhea, and abdominal cramps. It may also cause increased salivation, sweating, bronchoconstriction, and bradycardia. These effects are related to its cholinergic activity.

In cases of overdose or excessive use of neostigmine, symptoms of cholinergic crisis may occur, including profuse salivation, sweating, bronchoconstriction, bradycardia, and potentially life-threatening respiratory depression. Treatment involves discontinuing the drug, administering atropine as a competitive antagonist, and supportive measures as necessary.

#### *3.1.2.2 Physostigmine*

Physostigmine is a reversible acetylcholinesterase inhibitor classified as a parasympathomimetic drug. It increases the concentration of acetylcholine at cholinergic synapses by inhibiting the enzyme acetylcholinesterase, which breaks down acetylcholine. Physostigmine is available in various forms, including oral tablets and solutions for injection. The concentration and specific formulation may vary depending on the intended use.

Physostigmine can be administered orally, intramuscularly, or intravenously. It is rapidly absorbed and metabolized by esterases in the plasma and tissues. The elimination half-life is relatively short. Physostigmine inhibits acetylcholinesterase, allowing acetylcholine to accumulate and exert its effects at cholinergic synapses. It enhances cholinergic neurotransmission in various systems, including the central nervous system and peripheral organs.

Physostigmine is primarily used to manage anticholinergic toxicity, including poisoning by anticholinergic drugs, such as certain medications, plants, or insecticides. It can reverse the effects of excessive anticholinergic activity, such as delirium, hallucinations, and peripheral manifestations. Physostigmine is contraindicated in individuals with known hypersensitivity to the drug or those with mechanical gastrointestinal or urinary tract obstruction. It should be used cautiously in patients with asthma, epilepsy, or bradycardia. Side effects of physostigmine include gastrointestinal disturbances such as nausea, vomiting, diarrhea, and abdominal cramps. It may also cause increased salivation, sweating, bronchoconstriction, and bradycardia. These effects are related to its cholinergic activity.

In cases of excessive use of physostigmine, symptoms of cholinergic crisis may occur, including profuse salivation, sweating, bronchoconstriction, bradycardia, and potentially life-threatening respiratory depression. Treatment involves discontinuing the drug, administering atropine as a competitive antagonist, and supportive measures as necessary.

#### *3.1.2.3 Pyridostigmine*

Pyridostigmine is a reversible acetylcholinesterase inhibitor classified as a parasympathomimetic drug. It increases the concentration of acetylcholine at cholinergic synapses by inhibiting the enzyme acetylcholinesterase, which breaks down *Pharmacology of the Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.113006*

acetylcholine. Pyridostigmine is available in various forms, including oral tablets and extended-release formulations. The concentration and specific formulation may vary depending on the intended use.

Pyridostigmine is primarily administered orally and is well-absorbed from the gastrointestinal tract. It has a more prolonged action duration than other acetylcholinesterase inhibitors, allowing for less frequent dosing. Pyridostigmine inhibits acetylcholinesterase, increasing acetylcholine concentration and enhancing cholinergic neurotransmission. It primarily acts on skeletal muscles, improving muscle strength and tone. It also affects cholinergic neurotransmission in other systems, such as the gastrointestinal tract.

Therapeutically, pyridostigmine is primarily used to manage myasthenia gravis, a neuromuscular disorder characterized by muscle weakness. It helps improve muscle strength and function in individuals with this condition.

Pyridostigmine is contraindicated in individuals with known hypersensitivity to the drug or those with mechanical gastrointestinal or urinary tract obstruction. It should be used cautiously in patients with asthma, epilepsy, or bradycardia. Side effects of pyridostigmine include gastrointestinal disturbances such as nausea, vomiting, diarrhea, and abdominal cramps. It may also cause increased salivation, sweating, bronchoconstriction, and bradycardia. These effects are related to its cholinergic activity.

Overuse of pyridostigmine can lead to symptoms of cholinergic crisis may occur, including profuse salivation, sweating, bronchoconstriction, bradycardia, and potentially life-threatening respiratory depression. Treatment involves discontinuing the drug, administering atropine as a competitive antagonist, and supportive measures as necessary.

#### *3.1.2.4 Rivastigmine*

Rivastigmine is a reversible acetylcholinesterase inhibitor classified as a parasympathomimetic drug. It increases the concentration of acetylcholine at cholinergic synapses by inhibiting the enzyme acetylcholinesterase, which breaks down acetylcholine. Rivastigmine is available in oral capsules, oral solutions, and transdermal patches. The capsules and oral solution come in various strengths, typically 1.5–6 mg, while the transdermal patches are available in different doses.

Rivastigmine can be administered orally or transdermally. When given orally, it is well-absorbed from the gastrointestinal tract. It undergoes extensive metabolism in the liver, and the elimination half-life varies depending on the individual's genetic makeup. Rivastigmine inhibits acetylcholinesterase, increasing acetylcholine concentration and enhancing cholinergic neurotransmission. It primarily acts in the central nervous system, specifically targeting acetylcholinesterase in the brain.

Rivastigmine is primarily used for the treatment of mild to moderate Alzheimer's disease and Parkinson's disease dementia. It helps improve cognitive function in individuals with these conditions, including memory, attention, and daily living activities.

Rivastigmine is contraindicated in individuals with a known hypersensitivity to the drug or those with a history of hypersensitivity to carbamate derivatives. It should be used cautiously in patients with gastrointestinal conditions such as peptic ulcer disease or those at risk of developing bradycardia. It shares similar side effects to its sister medications.

In cases of overdose or excessive use of rivastigmine, symptoms of cholinergic crisis may occur, including profuse salivation, sweating, bronchoconstriction,

bradycardia, and potentially life-threatening respiratory depression. Treatment involves discontinuing the drug, administering atropine as a competitive antagonist, and supportive measures as necessary.

#### **3.2 Parasympatholytics**

Parasympatholytics are substances—or activities—that reduce the activity of the parasympathetic nervous system. They work by blocking the muscarinic receptors of the parasympathetic system. Most drugs with parasympatholytic properties are anticholinergics [29].

Parasympatholytic's pharmacodynamic effects include reduction of glandular secretion, dilatation of the pupil, paralysis of accommodation, increase of intraocular pressure, reduction of lacrimation, and more. These effects render parasympatholytics therapeutically valuable for treating slow heart rhythms, bronchioles constriction, and conditions such as benign prostatic hyperplasia, urinary retention, intestinal atony, and tachycardia [29]. It is worth mentioning, however, that parasympatholytics can interact with multiple drugs that can potentiate the antimuscarinic effect, such as antihistamines, neuroleptics, antidepressants, quinidine, or antiparkinson drugs [30].

Examples of parasympatholytics include atropine, methscopolamine bromide, flavoxate, orphenadrine, tiotropium, pinaverium, butylscopolamine, and anisodamine. However, atropine is the most used in the clinical setting.

#### *3.2.1 Atropine*

Atropine is classified as an anticholinergic or a parasympatholytic drug. Clinically, atropine is mainly indicated to treat bradyarrhythmias. Atropine also augments cardiac contractility by inhibiting cAMP-specific phosphodiesterase type 4, acting as a positive inotropic agent.

Atropine is a tropane alkaloid obtained from the deadly nightshade (*Atropa belladonna*) and other plants of the family Solanaceae. Its chemical formula is C17H23NO3, has a molecular weight of 289.4 g/mol (**Figure 2**), and is a racemic mixture of equimolar concentrations of (S)- and (R)-atropine. Atropine contains several functional groups, including an ester group, a hydroxyl group, and a tertiary amine group. The structure of atropine can be diagrammatically represented as benzene acetic acid, α-(hydroxymethyl)-8-methyl-azabicyclo {3.2. 1} oct-3-yl ester endo-(±). On hydrolysis, atropine gives (±)-tropic acid and tropine.

Atropine is an antimuscarinic agent that acts as a reversible, nonspecific antagonist of muscarinic receptors. It exerts its action by inhibiting the muscarinic actions of acetylcholine on structures innervated by postganglionic cholinergic nerves and smooth muscles, which respond to endogenous acetylcholine but are not so innervated. Atropine leads to both increased respiratory rate and depth, possibly due to the drug-induced inhibition of the vagus nerve. Generally, atropine counteracts the "rest and digest" activity of glands regulated by the parasympathetic nervous system.

Common medical uses of atropine include its role as an antisialagogue during surgery and anesthesia. It is also available in eye drops to treat uveitis and early amblyopia. Outside medicine, atropine is also used in the agricultural domain as a pesticide.

The pharmacological effects of atropine are due to binding to muscarinic acetylcholine receptors. Atropine is a competitive, reversible antagonist at muscarinic receptors, which blocks the effects of acetylcholine and other choline esters. Hence, *Pharmacology of the Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.113006*

atropine is used as an antidote for poisoning by muscarinic agents, including organophosphates and other drugs.

Atropine can cause several side effects, mild or severe, depending on the dose and the individual's response to the drug. Some of the most common side effects of atropine include dry mouth, blurred vision, dry eyes, photophobia, confusion, headache, dizziness, fatigue, tachycardia, palpitations, flushing, urinary hesitance or retention, constipation, nausea, vomiting, and so on.

#### **4. Conclusion**

In conclusion, exploring autonomic nervous system (ANS) pharmacology presented in this chapter provides a comprehensive understanding of the intricate interplay between neurotransmitters, receptors, and drugs within the sympathetic and parasympathetic divisions. This chapter unveils the complexity of ANS modulation by dissecting the mechanisms of both agonists and antagonists and delving into direct and indirect drug actions.

The broad spectrum of examples discussed underscores the significance of ANS pharmacology across various medical disciplines. From managing hypotension and other medical problems, the clinical applications are far-reaching. The meticulous analysis of pharmacokinetics, metabolism, adverse effects, and contraindications empowers healthcare professionals to make informed decisions that optimize patient care.

For anesthesiologists, in particular, this knowledge is indispensable. The ability to finely tune autonomic responses during procedures can significantly impact patient outcomes and safety. A robust understanding of ANS pharmacology is a cornerstone of any physician toolkit, enabling them to navigate the intricate balance of autonomic control in the perioperative setting.

#### **Conflict of interest**

All authors declare no conflict of interest.

*Topics in Autonomic Nervous System*

### **Author details**

Redha Waseem1 , Mogahed Ismail Hassan Hussein<sup>2</sup> , Tayseer Salih Mohamed Salih<sup>2</sup> and Sohel Mohamed Gamal Ahmed2 \*

1 Medical Education Department, Hamad Medical Corporation, Doha, Qatar

2 Department of Anaesthesiology, Intensive Care and Perioperative Medicine, Hamad Medical Corporation, Doha, Qatar

\*Address all correspondence to: sohelm@yahoo.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Pharmacology of the Autonomic Nervous System DOI: http://dx.doi.org/10.5772/intechopen.113006*

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Section 2

## Autonomic Influences on Pain and Cardiovascular Responses

#### **Chapter 3**

## The Role of Autonomic Nervous System in Pain Chronicity

*Dmitry Kruglov and Dermot McGuckin*

#### **Abstract**

The role of the autonomic nervous system (ANS) in chronic pain (CP) and in its chronicity is considered secondary and reactive to the nociceptive processes in the somatic nervous system (SomNS). However, research and clinical data strongly suggest the opposite. The ANS is an ancient, complex and ample part of the nervous system. It serves and controls visceral organs and somatic tissues. The ANS takes part in all aspects of all types of pain and influences its mechanisms at both peripheral and central levels. In this chapter we bring together the evidence from biomedical disciplines and clinical practice to support an alternative theory which contradicts the traditional views on the subject. We also raise questions which require further research to consolidate facts, advance our knowledge and improve treatment strategies for CP. The importance of this topic is difficult to overestimate because of the significant impact of CP on society and the lack of understanding, efficient therapy or cure.

**Keywords:** autonomic nervous system, autonomic, sympathetic, parasympathetic, chronicity, pain, chronic pain, visceral pain, somatic pain

#### **1. Introduction**

Chronic pain (CP) burdens a significant proportion of the population with pooled estimates for prevalence of 18–43% worldwide [1–3]. The vital role of the somatic nervous system (SomNS) in all types of pain is well recognised, but the importance of the autonomic nervous system (ANS) is mainly acknowledged in visceral or in 'sympathetically mediated' pain. The SomNS is perceived to be involved in all CP mechanisms and major dimensions of pain: physiological, sensory, affective, cognitive, behavioural, and sociocultural [4]. This is also true for the ANS, which is involved in major pain mechanisms and domains of all types of pain, not only visceral. A complete profile of ANS capability in CP formation has not been outlined, despite the accumulation of a sufficient body of evidence.

We planned this chapter as a brief conceptual narrative of a new notion of a comprehensive role of the ANS in CP. We will not didactically review the basic anatomy and physiology of the ANS, as we assume that anyone can find relevant information with its interpretation in current medical textbooks. Unfortunately, sometimes textbook authors present a simplified version of ANS structure and function. Without challenge, these deeply rooted views have been propagated from edition to edition or


**Table 1.**

*A brief summary of authors suggestions versus traditional views on the role of ANS in chronic pain development.*

referenced in other publications. For example, it is widely considered that a leading role in CP development belongs to the SomNS; the ANS only responds to acute or already established CP. This conclusion frequently follows the outcomes of experimental studies [5]. We propose the opposite: the ANS plays a primary role in any type of CP and in pain chronicity. **Table 1** summarises and compares our suggestions with traditional beliefs on the subject:

Our view challenges current understanding of ANS involvement in pain chronicity and opens new avenues for diagnosis, treatments, and outcome monitoring. Our opinion draws on basic facts and advanced knowledge of different fields including, but not limited to, evolutionary biology, anatomy, epidemiology, pathophysiology, diagnostics and western and traditional medicine (i.e., effects of treatment). Therefore, the structure of this chapter follows the above list of biomedical disciplines and encompasses illustrative examples of medical treatment, interventions, and investigations. Surprisingly, there are still many gaps in CP theory. By highlighting them and asking appropriate questions we hope to encourage independent thinking and to stimulate future research. This is aimed to improve an evidenced based approach to refractory CP conditions which burden our society.

#### **2. Evolutionary biology**

Acute pain is one of the essential phenomena in biology because it helps organisms to survive. Therefore, it must have emerged early in phylogenesis, and since then it has evolved along with the growing complexity of the nervous system. Our knowledge about nervous system evolution lacks satisfying clarity [6]. For example, it is not clear when the central nervous system (CNS) appeared or whether it debuted independently more than once in the history of animal life on Earth [7]. Also, we do not know for certain if the SomNS arrived before the ANS, or whether the sympathetic division of the ANS developed earlier than the parasympathetic division. Some embryological studies report that the oldest autonomic structures were unmyelinated vagal fibres from the dorsal motor nucleus of the vagus [8].

Scientists face significant difficulties answering the above questions as nervous tissue does not preserve well in fossils. To support any of these conflicting points, authors sometimes use a 'common sense' approach by asking what is more important, ability to 'fight or flight', or control of the internal milieu in a precise way. One theory

proposes that the "evolutionary origin of brainstem parasympathetic motor neurons out of branchial motor neurons, and spinal sympathetic motor neurons out of spinal motor neurons" [9].

However, comparison of ancient (but still living) species with modern organisms gives us essential facts for better understanding of evolutionary puzzles. For instance, sympathetic systems early in history employed acetylcholine (ACh) in postganglionic efferent neurons, and only later the majority of these fibres switched to noradrenaline (NA), except for sudomotor fibres. Certainly, the neuromediator change was reflected in sympathetic influence on some target organs with dual (sympathetic and parasympathetic) supply, when the stimulating effect mediated by ACh was passed over to the parasympathetic system.

ANS centres are located in phylogenetically ancient areas of the brain (hindbrain and midbrain) where autonomic, as well as the old somatic pain pathways (i.e., paleospinothalamic and archispinothalamic), terminate or make connections to; while the new somatosensory pain pathway (neospinothalamic) travels to the neocortex (forebrain).

*Conclusion:* SomNS and ANS have similar peripheral nociceptors, use the same neurotransmitters, and often share anatomical pathways and central connections. Both systems are of similar phylogenetic age [10, 11] and both should have been equally involved in pain processing, analysis, and responses.

#### **3. Anatomy**

Vast anatomical data help us to appreciate the fundamental role of the ANS in any type of CP. One can observe this in the complexity of the peripheral ANS: intricate structure and autonomy of local reflexes; abundancy (present in somatic and visceral peripheral nerves); diversity (variety of neuron types with different functions) [12]; and phylogenetic age of its spinal cord tracts and brain centres. Specificity in anatomical organisation of the ANS is the reason for precise homeostatic control: the efferent ANS (by its diversity of function and size) significantly "outweighs the somatic efferent pathways" [13]. Throughout this chapter we will continue comparing the ANS with the SomNS and draw your attention to their close interactions and inseparable activity. In this section we discuss the afferent, central, and efferent parts of the ANS and their significance for CP, but we will not cover the enteric part of the ANS.

#### **3.1 Afferent ANS**

Practically all somatic nerves contain autonomic fibres, and all of them are considered to be of efferent type (sudomotor, pilomotor and vasomotor). However, not all nerves contain somatic fibres; visceral nerves consist only of autonomic fibres. Therefore, any damage to peripheral nerve(s) will affect the performance of the peripheral ANS. This is also true for any type of damage at the level of the spinal cord as autonomic pain (sensory) tracts are in close proximity to somatic pathways. In consequence, when interventions treat peripheral nerves, nerve roots or epidural space, or spinal cord targets, the therapeutic effect on somatic and visceral/autonomic structures often cannot be differentiated.

Some publications advocate that primary visceral (sensory) neurons do not belong to the ANS, or if they do, they are not divided into sympathetic or parasympathetic fibres (despite visceral afferents travelling along sympathetic or parasympathetic

nerves). This concept is often oversimplified in the literature. In order to understand the matter, one has to explore: the definition of the ANS; types of fibres in the peripheral nervous system (somatic and autonomic) and connections their primary sensory neurons make in the spinal cord; ascending tracts (with their targets, number of neurons involved and their functions).

Definitions of the ANS which are currently used by various dictionaries, institutions, publications, and other sources of information, typically declare that it controls involuntary functions of the body (internal organs and glands). Some interpretations might add a conflicting statement, for example, characterising the ANS as a part of the peripheral nervous system only (a network of peripheral nerves and ganglions), or suggest that the ANS has only motor or efferent fibres. This ambiguity undermines the functional intricacy and capacity of the ANS, which consists of various afferents, spinal cord and brain tracts and a network of analysing and executing centres.

Afferent innervation for internal organs comes from vagal (85% of vagal fibres) and spinal (50% of splanchnic nerves fibres) visceral afferent neurons [14]. The neuron cell bodies of these afferents are located in dorsal root ganglions (DRG) or in cranial nerve (IX and X) ganglions. Vagal afferent neuron projections are organised viscerotopically within the solitary tract in the medulla and spinal visceral afferent neurons connect to Rexed laminae I and V and deeper layers of the spinal cord in a segmental order [14].

Different types of neurons outside and inside CNS carry molecule and transcription factor signatures. Vagal afferent and efferent neurons, sympathetic post-ganglionic and autonomic neurons in the CNS are defined by homeodomain transcription factor *Phox2b* [15, 16], but visceral spinal afferents are not. The latter, in contrast to somatic sensory neurons, do not typically target Rexed lamina II but give rise to different pain pathways within the spinal cord.

General visceral afferents which travel with sympathetic peripheral nerves have their cell bodies in DRGs and their axons synapse with the second-order sensory neurons predominantly in laminae I and V as well as deeper laminae (VII, VIII and X) of the spinal grey matter. Spinal afferents which project to viscera comprise only a few percent of all sensory neurons in DRGs, the vast majority of neurons there are of somatic nature. Visceral afferents which ascend along vagal nerves have their cell bodies in inferior (nodosum) ganglions and some in superior (jugular) ganglions. They project to the nucleus tractus solitarius (NTS) of the brainstem. We are not going to discuss autonomic afferents of VII (facial) and IX (glossopharyngeal) cranial nerves here.

Spinal visceral afferents are not morphologically different from somatic afferent neurons with cell bodies in DRGs. However, they might differ by their spinal cord pathways and a number of additional functions. These are local efferent and trophic roles, both related to antidromic transport and release of chemicals and mediators via the afferent terminals to the innervated cells to influence visceral activity. Vagal visceral afferents show a great deal of diversity and coding strategies in respect to the organs these neurons serve [17–20]. The conventional view is that nociceptive information does not get transferred via fibres within the vagus nerve. However, there are data supporting participation of vagal afferents in pain directly and indirectly. The latter might include interaction with sympathetic afferents at the cervical level [21], by inhibition of nociceptive dorsal horn activity, or by mediation of unpleasant symptoms (like nausea and bloating) which can exacerbate the pain experience. It is important to note that pelvic organs receive afferent innervation from two sources, both lumbar and sacral outputs. This list of possible mechanisms of visceral afferents

in pain transmission and modulation is not exhaustive. The majority of evidence is based on animal studies, but due to high level of phylogenetic conservation, the majority of anatomical and physiological data could be applied to humans.

#### **3.2 Ascending spinal cord tracts and vagal projections**

The complexity of the afferent part of ANS is not fully discovered. New research emerges every year clarifying some and giving start to new questions. However, the situation with ascending autonomic spinal cord pathways is even more perplexing. The confusion comes from traditional descriptions of the ascending sensory pathways, including:


For the purpose of this chapter, we allocate the highest significance to destination of the tracts and interconnections to other pathways. The latter feature enhances sensory experience and responses, including neuromodulating functions. It would be also useful to pay attention to evolutional order of appearance. Here we are not going to talk in detail about anatomical position and laterality. We will briefly mention this information only for selected pathways, as it is important in relation to accessibility by pain relieving interventions (their successes or failures).

Studies of nociceptive ascending spinal cord pathways confirmed existence of a large group of tracts. Not all of them end up in the brain cortex, many relay information to various areas of phylogenetically older parts of brain. Activation of these areas together with cortex centres contributes to multidimensional pain experience and its chronicity.

Fibres making the shortest (oligosynaptic) way to the cerebral cortex belong to relatively young structures (found in higher mammals), hence, forming the lateral spinothalamic (neospinothalamic) tract. It is monosynaptic on the segment to thalamus and, therefore, the fastest one. It brings sharp and well-localised sensation (small receptive fields) with a definitive quality (burning, stinging etc) of various intensity. These signals reach out to the somatosensory cortex; therefore, alert and warn consciousness. Neospinothalamic fibres are somatotopically organised (in all connections and at all levels), crossing to the opposite side in the spinal cord, and carry only somatosensory (not visceral) nociceptive information.

The older parallel tracts, named paleospinothalamic and archispinothalamic, include one or more synapses before thalamus. They make extensive connections to brainstem and other brain structures, lack somatotopic arrangements, target internuclear

thalamus nuclei, and start subconscious autonomic and descending neuromodulating reflexes. These pathways tap into the affective dimension of pain experience.

Autonomic nociceptive signals travel via older tracts. Primary autonomic sensory neurons converge their input on the next neuron together with somatosensory afferents. This happens in the grey matter of the spinal cord. Viscero-somatic wide dynamic range neurons take input from large diameter (myelinated skin afferents) and smaller (myelinated and non-myelinated skin and deep tissue afferents) and primary visceral afferents. Visceral, as well as somatic, nociceptive information (via convergent neurons) could be transmitted via multiple pathways:


Majority of the above anatomical discoveries were done with fine antero−/retrograde tracing techniques on animals (rats, cats, and monkeys) but often the results are transferrable to humans because of high level of phylogenetical conservation. The more recent studies revealed the presence of direct tracts connecting spinal cord with cortex and subcortical telencephalon bypassing thalamus.

The significance of simultaneous activation of parallel oligo- and polysynaptic ascending nociceptive pathways is not fully researched; however, we can appreciate its contribution to vivid reality of pain or pain relief in everyday life. This is also important prediction of outcome (and duration) of pain-relieving ablative procedures [22].

The above-mentioned ascending (relaying visceral nociceptive information) tracts project signals further by connecting to RVM, DRt, pontine noradrenergic groups, the hypothalamus, amygdala, the ventrolateral medulla VLM, the NTS, the rostral ventromedial medulla, PBN, the PAG, the thalamus and cortex (parietal somatosensory, prefrontal, frontal motor, orbital and cingulated). Majority of these destinations are parts of ANS. Some of the descending circuits which originate from PAG, DRt and some other centres exhibits suppression and facilitation at spinal cord synaptic sites of ascending tracts.

Visceral pain is also transferred by midline postsynaptic dorsal column (PSDC) pathway. The axons of PSDC neurons transmit pelvic visceral nociception, they travel uncrossed in the dorsal column. The primary termination of the visceral input of the PSDC cells is the dorsal column nucleus. Pelvic visceral cancer pain responds to limited or punctate surgical midline myelotomy, thoracic visceral pain—to a lesion at the lateral edge of the gracile fasciculus, and experimental pancreatic pain to complete bilateral lesion of the gracile fasciculus [23, 24].

#### **3.3 Central ANS**

As discussed earlier, ascending ANS spinal cord tracts project to many brain locations and, therefore, are capable of production of multiple effects including

#### *The Role of Autonomic Nervous System in Pain Chronicity DOI: http://dx.doi.org/10.5772/intechopen.112154*

descending pain control. Although, autonomic nociceptive pathways do not directly influence somatic pain, both systems meet at the spinal cord level (when primary afferents converge). Non-discriminative somatosensory nociception shares (phylogenetically old) pathways with visceral afferents and, therefore, highlight the same areas of the brain. Central and, therefore, efferent parts of ANS might be involved in visceral and at the same time in somatic pain due to such overlap. This is also reflected in the fact that "Pain Matrix", network of brain centres responsible for pain processing shares key areas with the ANS.

The traditional take on these relationships is that the ANS passively responds to acute or chronic pain. Observers measure a shift of autonomic balance between sympathetic or parasympathetic tone using heart rate variability (HRV) or other tests (sudomotor activity, muscle sympathetic activity etc) or simply vital signs (heart rate, rate of breathing). We consider this topic is largely uncovered and deserves more attention.

The ANS governs body functions and influences mental state, emotions (conscious and subconscious phenomenon) and feelings (conscious phenomenon). Its centres include those of forebrain (insular and anterior cingulate cortex, amygdala, hypothalamus) and brainstem (PAG, PBN, NTS, VLM and some other parts of medulla). There is a fast-growing body of publications showing the complex relationship between pain conditions and activity of ANS centres [25]. There are many examples of this co-existence in people with diseases of various systems: cardiovascular [26]; respiratory [27, 28]; digestive [29, 30]; genitourinary [31, 32]; immune [33]; thermoregulation [34]; cerebral circulation and headaches [35–37]; sleep and circadian rhythms [38, 39]. Many of the above publications and similar are observational studies (and rarely prospective) or reviews. It is difficult to say if chronic pain was the reason for recorded changes or if pre-existing disturbances in ANS functions created vulnerability to chronic pain.

We would argue that in real life, disturbing and disabling chronic pain cannot develop without disorder of ANS control. Disturbed autonomic functions and chronic pain are in reciprocal relationship often with positive feedback: chronic pain might be a reason for autonomic symptoms and developed symptoms might reinforce and facilitate duration of pain, and they usually trigger and exacerbate each other. Therefore, frequently pre-existing autonomic derangement (even mild) due to lifestyle or any other reasons makes people more vulnerable to development of chronic pain.

#### **3.4 Efferent ANS**

In many sources, the ANS is considered a binary structure with sympathetic and parasympathetic divisions. For simplicity of teaching, the efferent output of the ANS is divided into craniosacral (parasympathetic) and thoracolumbar (sympathetic), with opposite effects on target organs. However, this is true only for a few targets; many internal organs, glands, skin structures and blood vessels are innervated only by one division. If both divisions are involved, they do not produce opposite responses (stimulation vs. suppression) or each branch functions under different conditions. So, the correct view is that ANS divisions work synergistically to provide stability of the internal environment and provide with the adaptive responses for internal organs and somatic structures.

The anatomy of the efferent ANS is more complex than that of the somatic motor system. It has preganglionic segments, ganglions, and postganglionic motor neurons. Detailed structure of the efferent ANS is well described in the literature. We will touch only upon its relevance for CP development and perpetuation.

A vital point supporting our view is based on the involuntary reflexes which are delivered by autonomic efferent fibres to visceral and somatic targets. The afferent information for this activity comes from visceral or somatic sources, but the central nuclei belong to the ANS. Physiological reflexes might change under pathological conditions as well as the homeostatic control of internal organ functions. This could lead to a variety of symptoms and painful conditions. These changes might replace the original programs and become chronic through learning and neuroplasticity mechanisms. Altered function (i.e., bowel contraction, acid production or abnormal blood supply) might cause more pain and unpleasant sensations perceived through the ANS.

Pain inherently boosts pathological neuroplasticity through reinforcement learning where the insula plays an important role [40, 41]. The underlying mechanisms could negatively affect physiological training-induced neuroplasticity in physical tasks [42]. However, the precise effect of pain (acute, experimental, or chronic) on motor skill learning is the subject of debate as no strong evidence has been provided by research [43]. The longer the duration of reflex changes, and of pain, the more complex the situation becomes and the more challenging and less successful treatment is. At some point, the pain condition reaches an irreversible phase [44], when treatment pursues palliative outcomes.

Examples of altered reflexes affecting visceral organs could be Irritable Bowel Disease (IBS), where pain is linked to abnormal gut motility, or urinary bladder conditions, when disturbing symptoms of urgency, incontinence and spasms convolute with pain. As for somatic organs affected by pathologically-changed autonomic reflexes, (e.g., skin thermoregulation) the afferent part is mediated by somatosensory afferents, but the central control (hypothalamus) and efferent output (sudomotor, vasomotor and pilomotor nerve fibres) is provided by the ANS [45].

Recent research has revealed an interesting relationship between autonomic and somatic neurons, which might explain muscle weakness in certain painful conditions with altered sympathetic outflow to muscles, for example CRPS. Sympathetic efferent fibres innervate neuromuscular junctions and are vital for maintenance and function of synapses between somatic motor nerves and muscles [46, 47].

In *The Senses: A Comprehensive Reference, Second Edition (2020)*, chapter 5–21 [48] possible means by which the sympathetic nervous system could influence CP in somatic tissues are summarised. These are as follows: sympathetic-somatic afferent coupling; sensitisation of somatic nociceptors; neurogenic inflammation; and central changes in sympathetic pathways with the release of a variety of neuroactive substances and participation of neuroendocrine system. Earlie, Prof Jänig [49] discussed sympathetic (other than sudo−/pilomotor or vasoconstrictor) innervation of skin and deep somatic tissues, including muscles (vasodilators) and bones (peptidergic neurons, probably affecting mineralisation).

ANS involvement in musculoskeletal pain was investigated on the model of delayed onset muscle soreness (DOMS). Fleckenstein *et al* set out to discover to what extent sympathetically mediated pain (SMP) is responsible for exercise-induced acute muscle pain or damage in the upper limb [50]. They found that sympathetic regional (stellate ganglion) blockade causes pain relieving and anti-inflammatory effects. They suggested mechanisms for these effects which outlasted local anaesthetic block. These could be due to interruption of the vicious cycle of pain and local reflexes [51], allowing a reboot or a change in cytokine profile from pro- to anti-inflammatory [52]. There is also a possibility of changing of sympathetic and parasympathetic balance secondary to regional sympathetic outflow interruption. In fact, these effects might

follow any peripheral neural injection as autonomic fibres will always be affected by local anaesthetic due to the abundance of peripheral ANS fibres, as it was mentioned above.

*Conclusion:* Complexity (of all parts) and ample presence of the ANS; interconnections within and with the SomNS; active control of body functions (involved in pain mechanisms), emotions and behaviour; neuroplasticity of reflexes support evidence of global and fundamental role of the ANS in pain development and chronicity.

#### **4. Epidemiology**

Epidemiological studies have highlighted the prevalence of different pain conditions and their risk factors. Despite ongoing research, some of these facts (e.g., uneven gender distribution, drug sensitivity with therapeutic response, associations with other diseases) are difficult to explain. ANS imbalance might be one of the reasons we overlook.

Gender difference in pain prevalence, sensitivity and analgesic response has been reported in the literature [3, 53]. Women experience more severe pain and report it more frequently. They develop pain in more anatomical sites and for a longer time, with a higher prevalence across the majority of pain conditions. But some painful disorders are strikingly more frequently seen in women: fibromyalgia; pelvic and musculoskeletal pain; and temporo-mandibular joint pain amongst others. This is routinely attributed to genetic factors, sex hormone profile and cyclical changes in serum concentrations, tissue nerve density, and psychological factors, but rarely to ANS input.

Previous research has shown that women have a prevailing parasympathetic tone whereas men have a prevailing sympathetic tone. This difference disappears after the age of 55 years [54]. Sympathetic system activation has been reported in CP states. We do not know how the parasympathetic division contributes, but this certainly involves complex, multilevel and non-linear interrelationships between the sympathetic division and other determinants.

One of the conditions which is three to four times more common in females is complex regional pain syndrome (CRPS). Reported risk factors for CRPS include: history of migraine; osteoporosis; asthma; and angiotensin converting enzyme (ACE) inhibitor therapy. The latter two are associated with parasympathetic predominance, but osteoporosis is considered more related to sympathetic activation [55].

Neurotransmitters are used in experimental research to obtain strong evidence on the mode of activity of ANS structures in question. Drugs which we prescribe for treatment of any illness might intentionally (indication) or unintentionally (sideeffect) shift the balance between autonomic divisions. This is mediated through direct or indirect effects on adrenal and acetylcholine receptors in peripheral or central ANS. For instance, many antihypertensives suppress sympathetic outflow, whilst some antidepressants block and some opioids stimulate cholinergic pathways. Thus, treatment of comorbidities might affect pain conditions and vice versa. This is also important when pain-relieving drugs are chosen for a particular individual.

Time course of chronic diseases corresponds to constant changes which the ANS undergoes due to ageing, adjustment to climate, food habits, physical activity and many other factors. For example, asthma is more prevalent in boys, but later in life becomes more prevalent in women. This probably is due to a shift in autonomic balance which affects ANS airway control.

*Conclusion:* When we assess a case of CP it is essential to understand how it is related to excess or insufficient activity in each ANS division. This might influence our choice of drugs, interventions and other treatment methods, as well as help prognosticate. Coexisting medical conditions might give us a clue about autonomic balance and its dynamics, however, future research with appropriate questions and a fresh view on the problem might shed more light on the matter. The role of the parasympathetic system in developing CP has not been fully elucidated.

#### **5. Pathophysiology**

Practice makes perfect. This maxim is fully applicable to ANS design and functioning, but it requires a few clarifying comments. The ANS functions according to inherited programs (reflexes), and by learned behaviour patterns, which are established and maintained since birth and childhood [56]. This is achieved through learning by continuous feedback from internal and external environments, and neuroplastic changes which strengthen the neural circuits. Training of the nervous system is ongoing; it happens with or without our conscious acknowledgement and regardless of its value for the individual: regularly used activity gets reinforced; unused gets forgotten. For instance, one can develop insomnia when sleep routine is regularly disrupted by shift work or chaotic lifestyle. However, reintroduction of sleep hygiene will assist restoration of normal night sleep patterns. The same principle is employed in biofeedback bowel [57] or bladder training [58] for certain ANS disorders. In this subsection we discuss a few important consequences of autonomic dysfunction which impact on chronic pain development.

Any medical condition is associated with disturbed function of one or another organ, and therefore, with the disturbance of autonomic regulation of the corresponding physiological system. The opposite statement is also true: disturbed autonomic regulation will cause symptom development (into a medical condition) or prevent recovery from a condition-inducing event. This could be applied to acute pain as a symptom of a condition in question, or to chronic pain as a disease on its own.

A degree of autonomic disturbance might vary with different types of pain, the part(s) of nervous system involved, and anatomical region(s) affected. ANS dysfunction can be of local or global significance, and of mild or more severe presentation. We can associate diseases limited by anatomical region with the corresponding typical pain picture, but systemic medical conditions (e.g., diabetes, cardiovascular and lung diseases, rheumatoid arthritis, sickle cell disease) contribute to many chronic pain states. That is why the situation with diagnosis of disease causation and with recognition of factors leading to pain chronicity is not straightforward. Traditionally, abnormal ANS function and its diagnosis is overlooked in many (especially somatic) pain states, therefore the prescribed treatment often addresses only local symptoms, rather than pathophysiology of the underlying mechanisms.

For many chronic diseases we should recognise a reversible preliminary phase with subtle signs, which are usually below the threshold of current medical tests. Over a period of time autonomic regulation becomes progressively abnormal, but due to built-in robustness of the ANS, clinically significant deviation from medical norms might manifest years after. The preliminary phase is not usually identified, and underlying issues are not corrected. Partially this is because subclinical signs do not fall into pathological zones, but rather into domains of fitness or risk factors. This is a field of preventive medicine which, unfortunately, is largely unfamiliar to the general

public. The quality of life at this stage deteriorates slowly and patients usually adapt to these changes without noticing the ongoing problem.

The important question at this stage is whether a single organ autonomic dysfunction develops in isolation in a particular chronic pain state, or whether it is always a part of the more systemic trend. The diagnostic value of many available tests of ANS status in pre-clinical phase and in even in mild cases is questionable. Their results are frequently reported as negative (or mildly abnormal) as often subjective severity of symptoms of ANS dysfunction do not match objectively measured parameters [59].

From our clinical observations when patients are convinced that their symptoms fit into a picture of Postural Orthostatic Tachycardia Syndrome (POTS), interstitial cystitis or CRPS but investigations do not support their perceptions our attempts to reassure them often fail. At that point our misunderstanding of the situation, broken relationship with patient, and lack of tests with higher resolution or sensitivity (they define disease criteria) leads to delayed diagnosis and treatment. On the other hand, labelling patients with the above diagnoses without sufficient evidence may medicalise them for life and prevent recovery. This unfortunate dilemma is one of the innate weaknesses of medical practice. It is triggered by the patient's suffering from severe presenting symptoms.

The definition of suffering according to the Oxford English Dictionary is as follows: "the state of undergoing pain, distress, or hardship". In CP all three entities pain, distress and hardship—are intertwined, making it difficult to address them. The relationship between chronic pain, distress and hardship is well recognised. It dwells in emotional, social, and behavioural domains, and often is maintained by general symptoms (fatigue, chest tightness, mental fog and memory disturbances, sleep disorders and many others).

Sometimes the above constellation of symptoms is explained as an affective component of pain (linking it to the use of the old somatic nociceptive pathways), which is only partially true, as in fully developed CP we deal with neuroplasticity of nervous system where the ANS is responsible for many of these consequences [60–62]. Supporting evidence from research shows sympathetic hyperactivity in mental fatigue [63], significant and substantial ANS role in memory consolidation during sleep [64], association of mental fog and autonomic hyperarousal [65], abnormal autonomic sleep regulation in CP [66], and activation of autonomic pathways for chest pain and dyspnoea [67].

When medical professionals meet distressed patients who do not have clearly visible pathology which could explain the high degree of suffering, they often refer to these cases as those with functional (neurological) symptoms. However, many of these 'unexplained' symptoms could be due to disorganised activity of the ANS. We support the idea that suffering in CP could not happen without inherent participation of the ANS. This is because of a few reasons. ANS reaction to any pain or insult is inseparable to pain, even if pain is of somatic origin. Chronicity of pain and suffering is always at least partially driven by local or global dysfunction of the ANS. This includes control by emotional and behavioural centres, and often is not related to the severity of the index trauma.

CP patients develop maladaptive emotions and demonstrate changed behaviour. This includes poor coping and passive [68] strategies, fear-avoidance, and lack of motivation to invest efforts for their recovery, and social withdrawal. The ANS plays an important role in these changes. An experimental study [69] demonstrated that visceral pain response might relate to personality type, and it discovered sympathetic and parasympathetic co-activation in response to somatic and visceral pain. It is well known that the longer the chronic pain condition lasts and the more prominent are the patient's passive approach, sick role, and other maladaptive psychological trends, the worse these features become, and patients with these symptoms are less likely to improve.

Finally, we should not forget that autonomic dysfunction in control of inflammation and immunity [33, 70–72], endocrine system [48], circadian rhythms [39, 73–77], tissue regeneration [78–80], including ANS itself [81] also contributes to chronic pain development and its chronicity.

*Conclusion:* The reciprocal relationship between pain and ANS control of involuntary body functions, emotions, behaviour and body regeneration makes the ANS an integral and indispensable player in a drama of CP. The earliest phase of autonomic dysfunction is not recognised and corrected.

#### **6. Diagnostics**

In this subsection we review diagnostic investigations currently available for assessment of ANS activity and discuss their limitations. We also describe potential tests (based on autonomic features) which might be applicable for pain assessment.

Heart rate variability (HRV) is one such non-invasive tool which is used in lab research, for diagnostic purposes, or in everyday life to monitor cardiorespiratory fitness. HRV employs electrocardiography (ECG) or plethysmography (PPG) for measuring distances between electrical heart complexes (or beats) over a period of time. The raw data obtained from ECG or PPG are calculated into various indexes which (as per convention) might describe activity of ANS branches.

Although HRV uses cardiac electrical activity for calculations, it shows not only good predictability of mortality in the heart conditions, but also demonstrates abnormalities in ANS performance in many diseases and pain states. However, HRV is not condition-specific. Additionally, there is no validated scale that can diagnose a degree of autonomic dysfunction in a particular illness.

HRV is a cheap, easy to use and widely accepted tool. For a full analysis it requires only a budget peripheral wearable device and a smartphone application. The analysis is based on mathematical calculations: descriptive statistics for time domain and spectral analysis for frequency domain. The latter uses the term "power" in relation to the energy within a particular frequency band, which should not be confused with biological "strength" of ANS divisions.

We do not know what the power of the ANS is and how to physically measure it. With HRV we might see a snapshot of the balance between sympathetic and parasympathetic activity. Whether this balance is on proportionally suppressed or enhanced divisions it is not possible to say. Furthermore, autonomic activity might be disturbed only in one organ or system, or in case of global autonomic failure, different organs might be affected unequally. These points should be taken into consideration when interpreting a HRV report in relation to a particular pathology.

There have been attempts to match HRV with organ-specific physiological activity. For instance, by parallel measurement of HRV and of high-resolution manometry of colon [82]. This experiment showed parasympathetic activation and sympathetic withdrawal during triggered propulsive colonic activity.

Clinical tests require laboratory conditions for measurements, calibrated and medically certified equipment, and professional interpretations. These tests investigate a single organ or a system specific autonomic dysfunction, but they are often invasive and might require anaesthetic input. For example, those used in cardiovascular medicine (e.g., tilt table test with plasma catecholamine concentration measurement), in urology

(e.g., urodynamic tests), neurology (e.g., skin biopsy for nerve fibre density, nerve conduction studies, sudomotor activity and recordings of muscle sympathetic nerve activity), gastroenterology (e.g., gut motility, food transit, bacterial overgrowth).

Non-invasive options include disease specific questionnaires for organ function and thermography, a measurement of the surface temperature from the distance by thermal camera. The latter is useful in diseases with local change of blood supply, like in vascular abnormalities (vessel stenosis or arterio-venous malformation), regional sympathetic activity suppression (disease or local anaesthetic injection) or its excess (Raynaud's or iatrogenic). CP conditions which manifest with skin temperature changes include CRPS, neuropathic pain with neurogenic inflammation, ischaemic pain and some others [83].

Pupillometry (PPM) is another window into ANS activity. The size of the pupil depends upon the rhythmical activity of a sphincter (parasympathetic control) and dilator (sympathetic innervation), triggered by the amount of light reaching the retina. Despite a growing body of research in anaesthesia and acute perioperative pain management which use PPM for assessment of pain [84, 85] and drug effects, the utility of this non-invasive method has not been fully established.

Facial expressions (FE) and emotion recognition is a complex field (the ANS plays a major role in it) where stable prediction is not technically achieved. FE have been used in acute pain assessment for a long time, but not in CP. Computer vision techniques often employ facial action coding systems (FACS) which detect face geometry and movement patterns [86, 87].

We suggest that in CP sufferers, FE could be used to assess the effect of painrelieving intervention. According to clinical observations (unpublished data of the first author—DK), successful interventions in cancer pain dramatically change the quality of FE. For example, if a patient smiles before a procedure, it looks unnatural, forced or laboured. When the pain is relieved by intervention the smile becomes more natural with genuine facial mimic. This is a promising area for research of the role of the ANS in CP and pain relief with an objective and quantitative outcome.

Parameters of voice and of speech change under stress, emotional and cognitive load, pathological conditions and via ANS influence [88, 89]. A few voice-forming and modulating muscles are innervated by autonomic motor nerve fibres. Voice analysis could be used for monitoring of therapy and prediction of deterioration during the course of disease [90]. It is becoming more popular for pain assessment with the arrival of Artificial Intelligence (AI) based software [91].

*Conclusion:* Testing ANS state is essential in CP management; it demonstrates universal autonomic participation in CP. Clinical tests could be condition-specific, but invasive and demanding (equipment, staff etc.). Non-invasive methods are becoming more available for personal use (HRV, thermography), but some are still under-developed (pupillometry, facial and voice analysis). The resolution of existing tests is still low for the early recognition of pathology. Tests give a cross-sectional view (snapshot) on the condition but cannot provide longitudinal data for the evaluation of underlying pathophysiology. The latter could be addressed with the use of wearable multi-modal biosensing systems [92, 93].

#### **7. Treatment**

This section bears a dual purpose. It speculates on how the ANS could shape the outcomes of conventional pain-relieving procedures, and highlights the potential therapeutic interventions for disturbed ANS control. We discuss peripheral nerve blocks, epidural blocks and neuromodulation.

Local anaesthetic (LA) of sufficient concentration blocks nerve conduction allowing painless surgery. Unfortunately, pain returns if nerve blockade fades away. However, for post-operative analgesia significantly lower concentrations of LA than for surgery are required as there is no ongoing tissue damage.

In CP an injection of Lidocaine (LA) could provide a relieving effect of significantly longer duration (sometimes for several months or years) than the length of the nerve block [94].

First, we would like to describe thoracic differential epidural (TDE) blockade which is used as a diagnostic tool for abdominal pain to discriminate between somatic, visceral or central pain, and to predict response to visceral nerve block [95]. This intervention exploits two facts: smaller diameter visceral nociceptive afferents are blocked by a lower concentration of LA; and pain relief in visceral pain lasts longer than anaesthetic block duration [96]. This intervention showed that in many patients with pancreatitis, pain is of somatic nature [97].

Using the example of TDE, we might generalise that the therapeutic effect of epidural or peripheral nerve injection (beyond the LA duration) for musculoskeletal (somatic) pain could be due to concomitant sympathetic blockade. Epidurals, nerve root injections and peripheral nerve blocks produce sympathetic blockade in corresponding dermatomes or nerve distributions [98, 99].

Spinal cord stimulation (SCS) can provide pain relief and improvement of other symptoms in visceral and somatic pain by neuromodulation of various targets within the spinal cord. For example, SCS for refractory abdominal pain can improve chronic nausea and vomiting [100]. For neuropathic visceral abdominal pain, clinicians target the upper-mid thoracic level where splanchnic nerves emerge from the spinal cord. Improvement of gastroparesis and intestinal motility is highly suggestive of sympathetic blockade produced by SCS. However, available studies do not demonstrate consistent ANS reaction to SCS in sudomotor activity [101], heart rate variability (HRV), baroreceptor reflex sensitivity (BRS) and muscle sympathetic nerve activity (MSNA). Nor do they provide a plausible hypothesis for mechanisms of pain relief related to autonomic control [102]. This is another important area for future research.

Similarly to SCS, sacral nerve stimulation (SaNS) for pelvic organ dysfunction (bladder and rectal control) can also result in improvement in pain control [103] related to treated conditions.

Percutaneous tibial (somatic peripheral nerve) nerve stimulation (PTNS), which is used to improve urinary bladder control in Overactive Bladder, is an effective and minimally invasive technique [104]. It requires multiple sessions to achieve prolonged effect. PTNS also relieves chronic pelvic pain [105]. The mechanism of action is unknown but clinically it improves autonomic reflexes of the targeted organs. We can speculate about two possibilities:


Percutaneous or surgical vagal nerve stimulation has been suggested for many conditions caused by or associated with autonomic dysfunction [106–112], but the main indications are refractory epilepsy and certain mood disorders.

Non-medical options to maintain healthy ANS activity, which frequently involves parasympathetic stimulation and sympathetic withdrawal, include:


*Conclusion:* When planning pain-relieving interventions, healthcare professionals should consider treatment of underlying ANS dysfunction.

#### **8. Traditional medicine (TM)**

Traditional medical practices always acknowledge the complex relationship between organs and somatic tissues. It is reflected in diagnostic methods and in the holistic approach to treatment.

One of the unique methods used by many systems is the pulse diagnostic tool. It requires years to master but is claimed to provide invaluable information about any organ in the body. In general, it is probably an ancient equivalent of HRV, but much more sophisticated in the amount of detailed information it might provide an experienced practitioner.

Many traditions use a quasi-anatomical system: a whole-body map covered with lines or meridians (channels or vessels) with named points with very precise locations. The 'vital energy' freely flows through these structures controlling the activity of different physiological systems (lungs, bowel, liver, stomach etc.). There are 12 principal meridians in Traditional Chinese Medicine (TCM). There is no equivalent concept in western medicine.

The 24-hour biorhythm cycle allocates time of the highest and of the lowest activity to each channel. For example, the first meridian (Lungs) is the most active between 3 and 5 AM and 12 hours later (3 and 5 PM) it is in the lowest energy state. This circadian clock schedule correlates with clinical observations. For instance, maximum activity in the lung meridian corresponds to the peak of nocturnal asthma attacks. Maximum activity of the second meridian (Bowel) falls between 5 and 7 AM when people wake up after the night sleep and open their bowel. The next meridian (Stomach) is the most active when people normally have their breakfast, between 7 and 9 AM, and so on.

Abnormal flow of 'energy' (deficiency or excess and blockage) in one or more channels is the reason for symptoms of disease. Needling of the points according to the acupuncture recipe restores 'energy' flow and cures the disease and relieves pain (Yuan 2015). The choice of acupoints depends on the diagnosis, biorhythms and relationship between meridians. For example, neck and shoulder pain could be related to abnormal energy situations in gallbladder, bladder or large intestine meridians. Points could be chosen on these meridians or on others (via laws of relationship), around the painful area or distant to it; and they vary on a different time or day.

There are, of course, other than acupuncture treatment methods in TM: medications, breathing practices, postures and movements. The latter two could be organ

specific, and they are synchronised with breathing to optimise vital energy and its circulation.

*Conclusion:* TM uses a holistic approach. It operates at the levels of aetiology and pathophysiology rather than symptoms as western medicine does. Similarly to the ANS, the Meridian system functions according to biological rhythms and connects organs and somatic tissues (skin, muscles, bones, ligaments and joints).

#### **9. Conclusion**

CP is considered incurable as per current beliefs, personal experience of medical professionals and statistics. So, in a pain clinic, in the media and in professional literature, patients once diagnosed with CP receive the same message, they have to live with it. The present situation is maintained by the ignorance of already known facts. However, progress is being fuelled by breakthroughs in related fields across multiple disciplines. We propose that pain becomes chronic through significant input from the ANS. Autonomic dysfunction (subclinical or apparent, local or global) provides the background for suboptimal organ activity and subsequently leads to the development of chronic symptoms, including pain, or the transition from existing acute pain into CP.

We would like to bring attention to the mind-blowing complexity and ample presence [48, 49, 121] of the ANS in our lives, as well as to its important role in CP and pain chronicity. This chapter serves only to outline a topic which could easily fill a whole book and warrants ongoing research. Current evidence from evolutionary biology, anatomy, epidemiology, pathophysiology, diagnostics, and pain medicine (western and traditional) supports our view and paves the way for future work. However, even now, people might change their view on the topic and this could lead to improved outcomes in CP management. Therefore, the main takeaway message is that we have to seek the signs of ANS dysfunction in any CP condition and address the underlying mechanisms.

### **Conflict of interest**

The authors declare no conflict of interest.

*The Role of Autonomic Nervous System in Pain Chronicity DOI: http://dx.doi.org/10.5772/intechopen.112154*

#### **Author details**

Dmitry Kruglov1,2\* and Dermot McGuckin1,3

1 Pain Management Centre, National Hospital for Neurology and Neurosurgery, London, UK

2 University College London Hospital, London, UK

3 Research Department of Targeted Intervention, Division of Surgery and Interventional Science, University College London, London, UK

\*Address all correspondence to: dg\_kruglov@hotmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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**Chapter 4**

## Exploring Cardiac Responses of Pain and Distress

*Mona Elsayed and Elizabeth Barbara Torres*

#### **Abstract**

Pain and distress stand at the intersection of multiple health crises and are leading contributors to disability. Current pain assessments rely on self-reports—which assume a capacity to understand and verbalize mental/emotional states—and behavioral observation which can be subject to limitations and misinterpretation. Methods to evaluate pain/distress can be substantially enhanced with biometrics that incorporate the physiological aspects of the full pain experience. This chapter explores how induced pressure pain influences cardiac activity elicited via the autonomic nervous system. We aim to uncover signatures in cardiac responses via personalized analysis of the frequencies and the timings of the heart's inter-beat-interval. Autonomic responses such as cardiac activity serve as inevitable processes, which cannot be volitionally controlled—they exhibit a narrow range of dynamics, helping provide robust signatures of the body's responses to pain/distress. We find that pain elicits shifts in the heart rate variability metrics of the cardiac signal, alluding to changes in sympathetic and parasympathetic nervous system activation. Unique relationships are also observed between metrics obtained from the physiological data and self-reported pain ratings. The implications of this work are discussed in the context of precision medicine with possible applications in clinical populations such as autism.

**Keywords:** cardiac, pain, distress, sympathetic, biometric, ECG, HRV, autism, ASD

#### **1. Introduction**

Pain and distress are intrinsically undesirable experiences that are implicated in a variety of physical and mental illnesses. Pain stands at the intersection of multiple health crises, contributing to the opioid epidemic, health disparities, disability, and chronic pain [1, 2]. At least 125 million Americans suffer from acute or chronic pain, and this epidemic has been the root cause of the opioid crisis that arose in the late 1990s [2]. The increased use and misuse of opioids has led to over 47,000 deaths in the United States between 2013 and 2017 alone [3]. Thus, gaining a complete understanding of the neurobiological underpinnings of pain can lead to the most effective solutions to this epidemic [2].

Pain is yet to be explored and digitally characterized in terms of its effects on the autonomic nervous system (ANS). Aside from potential tissue damage, pain is associated with sensory, motor, cognitive, and social components [1]. Investigating pain thus requires multidisciplinary approaches that can integrate insights from

psychology (behavior, cognition, sensation, perception), neuroscience (nervous system physiology), and psychiatry (social/clinical research). An objective and noninvasive assessment of pain is also yet to be discovered and utilized in the clinical realm.

Traditional self-report techniques to assess pain are useful and convenient in the clinical realm however, they should be complemented with more objective approaches. Current pain assessments rely on surveys and questionnaires such as numerical rating scales, illustrative visual analog scales, and verbal rating scales which rely on semantic descriptors such as 'moderate' and 'severe' [4, 5]. Such assessments often assume the individual has the capacity to understand and verbalize mental/emotional states, making them disadvantageous for minimally verbal individuals or those with disabilities or neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Autistic children may experience difficulties in expressing their internal emotional states (hunger, pain, fatigue, etc.), leading to increased stress, tantrums/outbursts, and meltdowns. While external behavioral measures may be helpful in understanding such states, internal states may easily be masked or differently expressed across individuals, leading to interpretation errors. Thus, evaluating nervous system physiology in such populations can greatly enhance approaches that only rely on self-report measures and/or observing external behaviors.

In this work we evaluate the effect of pain on autonomic cardiac regulation, an inevitable process that cannot be consciously controlled during experimental tasks. The current study ultimately aims to develop digital biomarkers that can be used to detect pain and distress from cardiac activity elicited via the autonomic system. With the advent of wearable sensing technologies, it is possible to track physiologically relevant signals (electrocardiography/ECG) to help assess an individual's autonomic states. This study will utilize a multifaceted approach that investigates the effects of pain on cardiac reactivity in relation to self-reports of pain and pain sensitivity. With ECG sensors, we track the dynamics of heart signals and characterize how pain influences autonomic regulation. Pain-related biosignatures obtained via wearable sensors as the person

#### **Figure 1.**

*Integration of subjective and objective metrics to assess states of pain and distress. (A) Self-reports of pain and pain sensitivity levels are assessed by numeric rating scales traditionally used in healthcare settings to assess pain. (B) Wearable sensors that can track heart signals serve as a proxy for autonomic nervous system activity.*

*Exploring Cardiac Responses of Pain and Distress DOI: http://dx.doi.org/10.5772/intechopen.111890*

experiences physical pain are compared to the results of pain assessments self-reported by the individual. This integrative approach (**Figure 1**) leverages information from the autonomic systems to help in developing a clearer psychophysiological understanding of pain and ultimately aims to create robust techniques to assess pain and distress in those who have difficulty expressing it and in the general population.

#### **2. Cardiac signals as a proxy for autonomic nervous system (ANS) regulation**

Heart activity is under the dynamic control of the sympathetic cardiac nerves and the parasympathetic vagus nerve via the autonomic branches of the peripheral nervous system (NS). The ANS is largely responsible for maintaining the body's overall homeostasis [5]. The sympathetic NS works to increase heart rate while the parasympathetic NS serves as the brakes that turn the cardiac activity back to normal functioning. Sensory neurons between the brain, spinal cord, and cardiac muscles engage in continuous feedback loops, consistently influencing each other via reafferent signals (**Figure 2A**).

Fluctuations in sympathetic and parasympathetic activity can allude to unique physiological responses related to stress and anxiety. Exposure to painful stimuli and/ or discomfort and distress can activate the sympathetic NS which elicits the excitatory fight-or-flight response [6]. Previous studies on stress and autonomic responses such as cardiac reactivities provide insight into the physiology of pain sensation [7, 8]. Heart rate variability (HRV) analyses have proven reliable and advantageous in evaluating autonomic functions in this regard [9, 10]. HRV metrics represent the various statistics of the inter-beat- interval (IBI), the timing between beats in a cardiac signal (**Figure 2B**). HRV is widely used to evaluate sympathetic and parasympathetic

#### **Figure 2.**

*Cardiac responses as a proxy for autonomic nervous system function. (A) The sympathetic nervous system is responsible for increasing cardiac contractions during states of distress/anxiety while the parasympathetic nervous system serves as the brakes on the sympathetic system, modulating cardiac activity during resting states. Parasympathetic activity is guided by the vagal nerve, which governs heart rate variability (HRV) and allows for adaptive behaviors. Sensory neurons via the spinal cord allow for two-way communication between the heart and the brain. (B) Cardiac signals exhibit a unique QRS pattern where the timing between R-peaks (IBI) can serve as a proxy for sympathetic and parasympathetic activity.*

NS activity via various time and frequency-domain parameters. Improper balance between these two systems is often associated with cardiac pathologies such as strokes and heart attacks [9].

Previous work on HRV and stress have shown that when humans experience mental/physical strain, the parasympathetic NS's control over the heart decreases while sympathetic NS activity increases [11–13]. In such studies, physical strain was induced by having subjects perform intensive exercises [12], and mental strain was induced by asking subjects to solve difficult puzzles or arithmetic problems [13]. From these studies we find a clear interaction between the ANS and the nociceptive system as pain may often induce both mental and/or physical strain and distress [5, 6].

#### **2.1 Autonomic dysregulation: social and emotional components**

The autonomic nervous system plays an important role in socio-emotional learning and control [14]. Balanced vagal tone via the parasympathetic NS (responsible for modulating heart-rate) allows for swift engagement and disengagement with people, which is important for building social communication skills [15]. Social skills development during early childhood predicts a range of positive outcomes (in communication, assertiveness, role transitions, etc.) along with the formation and management of family and peer relationships throughout the lifespan [16]. Increased vagal tone is also associated with higher facial expressivity levels [17]. Decreased vagal tone can lead to dysregulated heart-rate (HR) modulation which may in turn lead to social interaction difficulties [15]. Imbalanced autonomic activity can also contribute to socio-emotional dysregulation during dyadic interactions in children diagnosed or at-risk for psychopathologies [18].

Symptoms of ASD are proposed to be associated with autonomic dysfunctions. Previous studies show that children with ASD and Intellectual Disability (ID) exhibit low parasympathetic activity during high anxiety conditions [19]. Autonomic dysregulation is also apparent in autistic children compared to typically developing (TD) controls [20]. When comparing the cardiac and electrodermal activity of autistics and neurotypicals, those with ASD exhibited dampened HR reactivity and skin conductance responses to visual and auditory social stimuli (face images and speech sounds) and during social interactions (role play) [21, 22]. More recent work demonstrated that the non-linear metrics of HRV show decreased autonomic modulation in autistic individuals compared to controls during resting conditions [23]. During facial expression tasks where subjects were asked to draw, interpret, and recognize different emotions, the ASD group showed lower parasympathetic modulation compared to controls, alluding to the elicitation of cognitive stress. Such autonomic dysregulation was also correlated with autism severity [24]. During social attention tasks, autistic subjects similarly showed reduced parasympathetic modulation, suggesting that autonomic dysregulation may underly social deficits in ASD [25].

Such findings are in line with the Polyvagal Theory which suggests that social behaviors may arise from the autonomic nervous system, with efficient vagal/parasympathetic control preventing sympathetic overactivation and thus contributing to better socio-emotional skills [26]. In ASD, the 'vagal brakes' on the sympathetic system may be compromised, leading to sympathetic hyperarousal and increased distress, which may impair behavioral adaptation/control and the ability to satisfactorily reciprocate social interactions [27]. Thus, assessing autonomic modulation may prove useful in understanding social–emotional responses, adaptive behaviors, and ultimately in screening and tracking symptoms associated with ASD.

#### **3. Experimental approach: autonomic biomarkers**

In this work, we explore the cardiac activity of neurotypical (TD) and autistic (ASD) individuals. Autonomic responses were proxied via the electrical activity of the heart. Electrocardiographic (ECG) activity was captured via wearable biosensors placed on the chest at the standardized lead II position via gel adhesives.

At the beginning of the study, TD participants were asked to rate their perceived pain sensitivity (PPS) relative to other people on a scale of 0–10, where zero represents complete insensitivity and a 10 represents extreme sensitivity [28].

Participants were seated at a table where they performed a Resting Task under control and experimental conditions. In the control condition of the study, the participants performed the Resting Task by sitting in a relaxed position and avoiding excess movement for about two minutes. This task was used to establish baseline autonomic NS activity as no movement or cognitive effort was required. During the experimental/pain condition of the study (only conducted with TD subjects), sustained pressure pain was introduced via a manual blood pressure cuff. This pain induction method serves as a modified version of the submaximal effort tourniquet test [28] which is found to mimic pathological pain [29]. In this procedure, the blood pressure cuff (standard sphygmomanometer/tourniquet) was placed around the non-dominant arm of the participant (above the elbow) and was gradually inflated to a pressure level of about 200 mmHg [30]. The cuff was inflated at this level for the entirety of the task and was deflated right after task completion. Right before cuff deflation, TD subjects verbally reported their pain level using a Numeric Rating Scale (NRS) ranging from 1 to 10, where a 1 indicates minimal to no pain, 4–6 indicates moderate pain, and a 10 indicates extreme pain [31]. Participants in the ASD group performed the Resting Task only under the control condition.

#### **3.1 Analytical approach to assess cardiac activity**

Electrocardiographic (ECG) data typically includes consecutive QRS complexes representing each heartbeat in the cardiac signal (**Figure 2B**). The R-peaks (sharp spikes) within QRS complexes are traditionally used to assess the timing between consecutive heartbeats (known as the R-R or inter-beat interval). Accurately detecting R-peaks is essential for assessing the fluctuations in the inter-beat interval (IBI) signal and in computing various heart rate variability (HRV) parameters. ECG signals may easily be corrupted by various artifacts such as baseline wandering and electrode movement [32]. To clean the raw ECG data, signal-processing filters were used to minimize excess noise/frequencies outside the range of a typical ECG recording [33]. After preprocessing of the ECG data, R-peaks were detected via a simple peak detection algorithm in MATLAB (MathWorks) software, and the IBI signal was obtained by computing the time between consecutive R-peaks. The statistics of the IBI signal were then evaluated via various frequency and time-domain metrics.

#### **3.2 Cardiac activity metrics of the autonomic system**

Changes in heart rate are the result of autonomic control via the sympathetic (excitatory) and parasympathetic (inhibitory) nervous systems (NS), which are informative in assessing how pain and distress influence the autonomic system [5]. HRV describes fluctuations in instantaneous heart rate (the oscillations between two consecutive heartbeats), where greater variability often reflects

enhanced vagal tone (heart rate regulation). The activities of the parasympathetic and sympathetic NS can be inferred from the Power Spectral Density (PSD) and Poincaré plots of the HRV signal (**Figure 3**). The high frequency (HF) component of the PSD (150–400 mHz range) is associated with parasympathetic activity and a general decrease in heart rate [34]. The low frequency (LF) component of the PSD (40–150 mHz range) is associated with sympathetic NS activity and blood pressure control [34]. The LF/HF ratio reflects the sympatho-vagal balance – the contribution of the sympathetic NS in controlling the heart compared to the parasympathetic NS [9]. Increases in the ratio between the LF and HF components (LF/HF ratio) have been previously associated with stress and intense exercise [12, 13]. The LF and HF components were computed by integrating the PSD over the associated frequency range.

Poincaré plots are also used to assess sympathetic and parasympathetic activation via time-domain metrics. Pioncaré plots serve as a geometrical and nonlinear method to assess the dynamics of HRV and are formed via a scatter of the IBI interval against the preceding IBI interval [35]. The width of the scatter is used to determine the SD1 parameter, which reflects parasympathetic NS activity and is correlated with HF power [36, 37]. The length of the scatter is used to determine the SD2 parameter, which reflects sympathetic NS activity and is correlated with LF power [36].

The PhysioNet Cardiovascular Signal Toolbox was also used to assess the ECG time series. This open-source toolbox is designed to assess HRV via standardized algorithms [38]. With this toolbox we windowed the IBI series and obtained a distribution of LF, HF, LF/HF, SD1, SD2, and SD2/SD1 parameters. To better visualize which frequencies (in the LF and HF ranges) dominated the cardiac signal across time, continuous wavelet transforms (CWT) or magnitude scalograms were used to visualize and evaluate temporal changes in frequency power and provide a personalized assessment of the autonomic activity (**Figure 4A**).

#### **Figure 3.**

*Analytical pipeline to assess autonomic activity via cardiac signals. The timing between R peaks (red markers) of the original ECG data are extracted to obtain the IBI signal. The IBI signal is then assessed in the frequency domain (power spectrum) to obtain LF (sympathetic) and HF (parasympathetic) components. The same IBI signal is assessed in the time domain (Poincaré plot) to obtain the SD2 (sympathetic) and SD1 (parasympathetic) parameters.*

*Exploring Cardiac Responses of Pain and Distress DOI: http://dx.doi.org/10.5772/intechopen.111890*

#### **Figure 4.**

*Cardiac responses across control and pain conditions in TD subjects. (A) CWT plots (or magnitude scalograms of the frequencies present in the heart signal across time) demonstrate higher magnitudes in the LF range corresponding to sympathetic nervous system activation in the pain compared to the control condition. (B) Violin plots from data accumulated across subjects demonstrate that the LF/HF and SD2/SD1 ratios (indicative of sympathetic NS arousal and/or parasympathetic NS inhibition) of the control vs. pain condition arise from different distributions, with the median for these ratios being higher for the pain condition. (C) Schematic of the effects of pain and pain-related distress on the autonomic system and the corresponding changes observed in the HRV metrics in the time (SD2 and SD1) and frequency (LF and HF) domains.*

#### **3.3 Integrating cardiac biometrics with self-report data**

To explore the relationship between self-reported responses and the cardiac biometric data, scatter plots were made comparing each subject's ratings against the absolute difference between the HRV metrics (obtained from the experimental and control conditions). Numeric scale pain ratings of the experimentally induced pressure pain were also compared to the perceived pain sensitivity (PPS) ratings. Scatterplots were used to assess possible relationships between PPS ratings and changes in the biometrics obtained from the cardiac signal. Such methods allow us to evaluate the correspondence between physiological metrics and common psychological assessments of pain.

#### **4. Results: autonomic responses of distress**

#### **4.1 Heart rate variability (frequency + time-domain metrics)**

HRV results were compared across control and pain conditions for TD subjects (**Figure 4**). Frequency-domain analysis of the IBI data demonstrated that the pain condition often elicited an increase in LF power (corresponding to sympathetic NS activation) and/or a decrease in HF power (corresponding to parasympathetic NS activity) for TD subjects. Such frequency changes can be visualized qualitatively across the entirety of the task via CWT plots (**Figure 4A**). The LF/HF and SD2/ SD1 ratios (where an increase represents sympathetic NS activation or parasympathetic NS inhibition) were also computed across the control and pain conditions. Violin plots demonstrated changes in the shape of the probability density of these

parameters across participants (**Figure 4B**). For the pain condition, there was a general increase in both ratios based on data accumulated across TD subjects. Nonparametric Kruskal-Wallis tests indicated that the LF/HF and SD2/SD1 ratios across the control and pain conditions come from significantly different distributions: *χ* 2 (1,175) =14.37, *p* < 0.001 and *χ* 2 (1,179) = 12.44, *p* < 0.001, respectively.

#### *4.1.1 The unique case of a subject with chronic pain*

Heart data analyses for a subject known to experience chronic pain led to unique findings compared to the remaining participants. The CWT plots of this subject consistently exhibited high LF power specifically in the 100–150 mHz range (**Figure 5**). This pattern was observed across both control and pain conditions. It is important to note that while this participant did experience the experimentally induced pressure sensation during the pain condition, they were accustomed to experiencing a consistent level of pain throughout their daily life. These results emphasize the importance of analyzing at the biophysical data in a personalized manner before calculating summary statistics or assessing trends based on the entire sample.

#### **4.2 Self-reported pain ratings and HRV parameters**

When exploring the self-reported measures, we find that perceived pain sensitivity (PPS) generally corresponded with the pain ratings reported during the study (**Figure 6A**). This indicated that participants could accurately approximate their pain sensitivity levels compared to others. To assess the relationship between objective and self-reported measures, we compared the HRV parameters of the cardiac signal with each subject's ratings during the pain condition of the Resting Task. The absolute difference (Diff) in the SD2 parameter (indicative of sympathetic NS activity) was computed to assess how much each subjects' cardiac signatures during the pain experience deviated from those of the control condition (SD2 Diff). This deviation in the SD2 parameter appeared to positively correlate with self-reported pain ratings and

#### **Figure 5.**

*Cardiac activity of a participant with chronic pain. CWT plots consistently showed high magnitude in the 100–150 mHZ range (corresponding to LF power) regardless of whether pressure pain was or was not (control condition) introduced during the resting task.*

*Exploring Cardiac Responses of Pain and Distress DOI: http://dx.doi.org/10.5772/intechopen.111890*

#### **Figure 6.**

*Integrating self-reported measures with autonomic HRV biometrics. (A) Participants with higher perceived pain sensitivity (PPS) levels typically reported the induced pressure pain to be of a higher intensity on the 1–10 numeric rating scale. (B) The absolute difference in the SD2 biometric between the control and pain condition (SD2 Diff) generally corresponded with higher self-reported pain ratings and perceived pain sensitivity levels.*

#### **Figure 7.**

*Comparing cardiac responses of TD and ASD participants. (A) Cardiac activity of neurotypical (TD) participants during the pain condition exhibited higher power in the LF range of the magnitude scalogram compared to the control condition where no pressure pain was induced. (B) For ASD participants at baseline, we observe a similar pattern of higher power in the LF range that mimics what is observed in TD participants during the pain condition.*

perceived pain sensitivity (**Figure 6B-C**). This indicates that it is possible to elucidate relationships between objective and subjective measures of pain sensation.

#### **4.3 Autonomic responses in ASD subjects at baseline**

When assessing the cardiac activity of autistic participants during the control condition of the Resting Task, we see a pattern in the CWT magnitude scalograms that mimics what was observed in TD participants at baseline (**Figure 7**). This indicated that autistic individuals may be experiencing sympathetic hyperarousal or have dampened parasympathetic nervous system regulation at baseline.

#### **5. Discussion**

The goal of this work was to assess changes in autonomic nervous system responses when the body experienced physical pain. We aimed to determine whether pain could be objectively characterized via heart rate variability metrics and how these metrics would compare to self-reported measures of pain. The pressure pain's influence on cardiac activity was apparent in the HRV metrics of the ECG signal. In the TD group, the induced pain led to increases in LF power. For most subjects, we also saw a corresponding decrease in HF power, which ultimately led to an increased LF/HF ratio. Such changes in the frequency-domain metrics suggest that the pressure pain led to sympathetic nervous system activation [25]. Interestingly, when assessing the cardiac activity of a participant who experienced chronic pain, we detected a consistent band of LF power (sympathetic activity) dominating the signal across both the control and pain conditions. This may indicate that the subject's chronic pain elicits a cardiac response that is impervious to the experimentally induced pressure pain. The finding that this subject's baseline cardiac activity resembles that of TD subjects under the pain condition helps provide some external validity to the pain induction procedure and provides further evidence for how pain can lead to increases in LF power and the LF/HF ratio. When evaluating HRV metrics in the time-domain via Poincaré plots, we generally observed an increase in the SD2, a decrease in the SD1, and an increase in the SD2/SD1 ratio, each of which are associated with sympathetic NS overdrive [35]. We find similar patterns of sympathetic hyperarousal in autistic individuals at baseline.

In this work, the physiological HRV metrics also complemented self-report measures. In general, we found that subjects have an accurate perception of their pain sensitivity level, as their PPS ratings appeared to positively correlate with their self-reported pain ratings. When assessing the relation between HRV metrics of the cardiac signal and the self-reported responses, we observed that higher deviations in the SD2 between the baseline and pain condition corresponded to higher PPS and numeric pain ratings. Such findings indicate that objective and nonlinear measures of HRV such as the SD2 parameter can be informative in understanding an individual's pain levels and their general pain sensitivity.

#### **5.1 Study implications and future work**

With this work we can begin to understand the relationship between pain, psychological responses, and physiological activity. This study demonstrated that the influence of pain on the body can be characterized via the statistics obtained from

#### *Exploring Cardiac Responses of Pain and Distress DOI: http://dx.doi.org/10.5772/intechopen.111890*

cardiac signals and that such biometrics can inform current subjective approaches. The findings of this study have several clinical implications. Characterizing the effects of sustained pressure on cardiac functioning of healthy individuals can help in the development of accurate and objective digital biomarkers of pain sensation. Such objective assessments are vital to understanding whether and how individuals who may have difficulty communicating their pain – such as those with Autism Spectrum Disorder (1 of 59 in the US), Intellectual Disability, or impaired communication skills – experience pain under normal conditions [39–41]. Individuals with Intellectual Disability experience chronic pain that often goes unnoticed and untreated [41]. Autistic individuals often exhibit higher sensitivity to painful stimuli and generally have trouble communicating their emotional or mental states to others [39, 40]. During states of sympathetic overdrive (as commonly observed in ASD), it is difficult for the parasympathetic system to acquire the predictability needed for expressing internal mental and emotional states and reciprocating social interactions. Thus, there is an urgent need to develop objective methods to characterize and understand pain and distress in such individuals. Detecting any form of autonomic dysregulation may indeed help us understand the hypersensitivities and socio-emotional difficulties observed in ASD. Such assessments can ultimately contribute to early diagnoses and mitigated distress for families and non-speaking populations at large.

Pain is a multi-faceted construct, associated with multiple biological, sensory, cognitive, and social components [1]. Thus, it must be explored via a multidimensional psychophysiological approach. Future work aims to explore the sensory-motor and socio-emotional aspects of the pain experience. This can be done by assessing the facial expression and movement activity of participants as they perform motorcognitive tasks while experiencing pain. While the autonomic system provides a bounty of information about the underlying physiology of pain and distress, we cannot forget about the contribution of the overarching peripheral nervous system that works to guide sensation, perception, decision-making, movement, and overall behavior. Recent work by Ryu and Torres has indeed connected voluntary control of motor output to the autonomic system in neurotypical individuals [42]. This work demonstrated that the heart plays a vital role in agency, highlighting the delicate balance between autonomy and control. From this previous work we learned that the cardiac signal leads the motor signal when a movement is intended but lags it when the movement is unintended [42]. Besides differentiating between deliberate and spontaneous motions, the cardiac code can help us begin the path of characterizing and distinguishing different types of afferent feedback, including those from kinesthetic and somatic pain signals. Further evaluating the autonomic system can help us deconvolve the continuous efferent stream of voluntary movements from the afferent consequences that they themselves cause. Understanding such relations will help us derive causal mechanisms of the nervous systems, beyond mere correlations. Such work highlights the importance of exploring the peripheral nervous system (including the autonomic branches) as a whole, as it can play key roles in the multi-faceted nature of pain and distress.

#### **6. Conclusions**

This work provides an innovative approach to better understand the mechanisms by which experimentally induced pain – that mimics pathological pain [28] – influences the autonomic nervous system via evaluating cardiac signals. From this work,

we learn that pain can interfere with autonomic regulation, eliciting sympathetic overdrive. The cardiac reactivities also appear to correspond with self-reports of pain and pain sensitivity. The observed patterns of autonomic dysregulation (sympathetic hyperarousal) during the physical pain experience in TD individuals mimic the cardiac responses observed in ASD participants at baseline. The unique results observed in ASD and chronic pain subjects highlight the importance of a personalized approach to assessing data. Such methodologies lend themselves to the Precision Medicine platform which helps inform the development of personalized treatments [43]. Our psychophysiological approach can ultimately help create robust techniques to detect pain and aid in the development of personalized interventions that are tailored to each individual's autonomic functioning. The added convenience of using wearable sensors makes this technique flexible and translatable for use in healthcare settings. The digital biometrics explored in this work open a new realm of research that can help us scientifically understand and characterize pain in a variety of neurodevelopmental disorders and in those with communication disabilities. Ultimately, such research can lead to new methods of identifying and alleviating pain and distress, improving the quality of life of individuals across the globe.

#### **Additional information**

Portions of this book chapter are derived from the thesis project titled "Characterization of Psychophysiological Responses to Pressure Pain" authored by Mona Elsayed, which is available on the Rutgers University repository platforms, dated October 2021. The thesis work has not been peer-reviewed nor published elsewhere.

#### **Acknowledgements**

We thank all members of the Sensory Motor Integration Lab (SMIL), and all the families and participants who made this work possible. This work was supported by the Nancy Lurie Marks Family Foundation Development Career Award to EBT and the New Jersey Governor's Council for Research and Treatment of Autism to EBT (CAUT14APL018).

#### **Conflict of interest**

The authors declare no conflict of interest.

*Exploring Cardiac Responses of Pain and Distress DOI: http://dx.doi.org/10.5772/intechopen.111890*

#### **Author details**

Mona Elsayed\* and Elizabeth Barbara Torres Rutgers University, Piscataway, NJ, USA

\*Address all correspondence to: mona.elsayed@rutgers.edu

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### Section 3
