**1. Introduction**

Despite considerable efforts made by the medical research community and pharmaceutical industry to develop effective therapeutical treatments aimed to treat chronic visceral pain resulted from functional disease, there is little progress to date. Functional syndromes are estimated to affect up to 15–20% of the population worldwide. Symptom description of interstitial cystitis/painful bladder syndrome (IC/PBS, urgency, frequency, and bladder pain generally relieved by voiding) is parallel to the description of irritable bowel syndrome-diarrhea (IBS-D) predominance (urgency, frequency and abdominal pain) relieved by defecation. IBS stands in contrast to a bowel's structural disorder: unlike ulcerative colitis and Crohn's

© 2016 The Author(s). Licensee InTech. 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. © 2018 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.

disease, which are forms of inflammatory bowel disease (IBD), it does not cause changes in bowel tissue. The cause of functional disorders is unknown. Chronic abdominal complaints are without a structural or biochemical cause. Bloating, mucous in stools, diarrhea, constipation or alternating diarrhea and constipation, depression, anxiety or stress are also common symptoms of IBS. Hypersensitivity of visceral primary afferent neurons could result from excessive production of different modulatory neurotransmitters in response to changes in their signal transduction pathways [1]. Nociceptors are small-to-medium size dorsal root ganglia (DRG) neurons, whose peripheral processes detect nociceptive physical and chemical stimuli. There is often no clear relationship between the severity of the chronic pelvic pain and pathology in the pelvic viscera, and there are also noticeable gender differences in the prevalence of functional diseases that affect more women than men. Most of studies in this area were focused on the central nervous system (CNS); however, our recent data that estrogen can gate primary afferent response to modulate nociception support the idea about the involvement of the peripheral nervous system (PNS) in the etiology of a wide range of the functional and inflammatory diseases [2]. This potentially could involve neuroplastic changes in primary sensory neurons and can be a novel target for therapeutic interventions for patients suffering from chronic visceral pain associated with functional diseases. Despite a successful reduction of pain using available analgesics, visceral pain relapses in most patients. Currently, it is a time for paradigm shift what we consider as visceral nociception, and in this report, author looks for possible new mechanisms of peripheral modulation of primary afferent sensory neurons in development of chronic pelvic pain.

modulating intestinal movement and the perception of visceral pain. An imbalance of serotonin in the gut, an improper reaction of the digestive system to serotonin, or a faulty serotoninergic network between the gut and the brain may be a cause of depression associated with functional diseases. Enteric nervous systems that innervate gastrointestinal tract include differentiated (visceral) primary afferent neurons that innervate intrinsic and extrinsic pathways implicated in the pathology of many inflammatory as well as functional diseases. There is a noticeable correlation between inflammation induced by gut infection and symptom occurrence of functional disorders such as IBS [5]. New data changed the previous paradigm that each primary afferent neuron innervates only one viscus. The concept of viscero-visceral cross-sensitization is well accepted and has been documented clinically [6]. Inflammation in one organ can induce peripheral (in addition to central) sensitization affecting another viscera. Therefore, nociceptive mechanisms involved in the progression of functional diseases are complicated by comorbid disorders. Both components of pain—discriminative and affective—concomitantly affect motor and cognitive systems. These systems can be gated by estro-

The chronic pelvic pain (CPP) from pelvic structures is more prevalent in female subjects compared to males. In clinical studies, this sexual dimorphism is well recognized: the incidence of functional disorders is 2–3 times higher in women with IBS and even greater with IC/PBS. A large body of literature supports that concept indicating estrogen modulation of different nociceptive pathways [2]. In our previous studies, we found that estrogen receptors (ERα and ERβ) are present in small-to-medium size DRG neurons (presumably nociceptors) and

can act in the periphery to modulate nociception [1]. Specifically, E2

neurons to modulate L-type VGCC and through group II metabotropic glutamate receptors

antinociceptive opioids such as enkephalins, β-endorphin and pronociceptive nociceptin/ orphanin. Furthermore, our hypothesis is that increased nociceptive input from an inflamed organ (i.e. uterus) sensitizes neurons that receive convergent input from an unaffected organ (i.e. colon). In summary, our data suggest that potential site of visceral cross-sensitivity is the dorsal root ganglion [9]. DRG neurons could be responsible for changes observed in the perception of pain during the etiology of different functional syndromes associated with pain.

ent neurons. Both estrogen receptors (ERα and ERβ) are present in DRG and visceral pain is affected by hormonal level in cycling females [1, 2]. Even a large body of literature supports

nism remains unresolved. Within the context of our hypothesis, E2 modulation of nociceptive response depends on the type of pain, its durations and the involvement of other nociceptive-

modulates nociceptive responses in pelvic pain syndromes, the exact mecha-

) [7], which correlated well with the

acts in DRG

sensitive. Our data clearly suggest that in addition to CNS

Neuroplasticity of Primary Sensory Neurons in Visceral Nociception

http://dx.doi.org/10.5772/intechopen.73699

3

directly influences the functions of primary affer-

modulates neuronal excitability is through the interaction with

gen to modulate perception of pain, pain threshold and tolerance.

**3. Gender differences in visceral pain**

ATP-sensitive DRG neurons respond to 17β-estradiol (E2

idea that visceral afferents are E2

Several lines of evidence indicate that E2

[8]. One prominent way E2

actions, E2

the idea that E2

mediated mechanisms.

## **2. Neuroplasticity in peripheral nervous system**

Traditionally, the main mechanism involved in development of chronic visceral pain is thought to be neuroinflammation. This pathway effects peripheral and central nerve sensitization and/or dysfunction of inhibitory descending pathways [3]. However, in clinical studies, visceral nociception strongly affects negative sensations that difficult to correlate with visceral traumata. Most nociceptive systems involved in peripheral sensitization originate in free sensory nerve endings of target organs that send their signals toward primary afferent sensory neurons within the lumbar-sacral regions of dorsal root ganglia (L1 -S3 DRG).

Visceral sensitization may develop as a result of interaction between the nervous and immune systems. All visceral afferents can be sensitized by proinflammatory mediators, such as serotonin, histamine, nitric oxide and ATP, leading to neuropathic hyperalgesia. During inflammation, mast cells and leukocytes secrete inflammatory mediators such as cytokines and prostaglandins that activate polymodal nociceptors triggering the response of normally silent mechano-insensitive receptors. Mast cell mediators can also activate vanilloid receptors (TRPV1), purinergic (P2X<sup>3</sup> ) and bradykinin (BK2) at PNS, causing hyperalgesia.

The serotonergic pathway, one of the main inhibitory mechanisms in the CNS, may also be functionally important in facilitating peripherally mediated visceral pain [4]. Most antidepressants gradually increase serotonin level in the brain. Indeed, depression has been reported to be associated with immunosuppression. Serotonin plays a major role in the gut-brain axis by modulating intestinal movement and the perception of visceral pain. An imbalance of serotonin in the gut, an improper reaction of the digestive system to serotonin, or a faulty serotoninergic network between the gut and the brain may be a cause of depression associated with functional diseases. Enteric nervous systems that innervate gastrointestinal tract include differentiated (visceral) primary afferent neurons that innervate intrinsic and extrinsic pathways implicated in the pathology of many inflammatory as well as functional diseases. There is a noticeable correlation between inflammation induced by gut infection and symptom occurrence of functional disorders such as IBS [5]. New data changed the previous paradigm that each primary afferent neuron innervates only one viscus. The concept of viscero-visceral cross-sensitization is well accepted and has been documented clinically [6]. Inflammation in one organ can induce peripheral (in addition to central) sensitization affecting another viscera. Therefore, nociceptive mechanisms involved in the progression of functional diseases are complicated by comorbid disorders. Both components of pain—discriminative and affective—concomitantly affect motor and cognitive systems. These systems can be gated by estrogen to modulate perception of pain, pain threshold and tolerance.

#### **3. Gender differences in visceral pain**

disease, which are forms of inflammatory bowel disease (IBD), it does not cause changes in bowel tissue. The cause of functional disorders is unknown. Chronic abdominal complaints are without a structural or biochemical cause. Bloating, mucous in stools, diarrhea, constipation or alternating diarrhea and constipation, depression, anxiety or stress are also common symptoms of IBS. Hypersensitivity of visceral primary afferent neurons could result from excessive production of different modulatory neurotransmitters in response to changes in their signal transduction pathways [1]. Nociceptors are small-to-medium size dorsal root ganglia (DRG) neurons, whose peripheral processes detect nociceptive physical and chemical stimuli. There is often no clear relationship between the severity of the chronic pelvic pain and pathology in the pelvic viscera, and there are also noticeable gender differences in the prevalence of functional diseases that affect more women than men. Most of studies in this area were focused on the central nervous system (CNS); however, our recent data that estrogen can gate primary afferent response to modulate nociception support the idea about the involvement of the peripheral nervous system (PNS) in the etiology of a wide range of the functional and inflammatory diseases [2]. This potentially could involve neuroplastic changes in primary sensory neurons and can be a novel target for therapeutic interventions for patients suffering from chronic visceral pain associated with functional diseases. Despite a successful reduction of pain using available analgesics, visceral pain relapses in most patients. Currently, it is a time for paradigm shift what we consider as visceral nociception, and in this report, author looks for possible new mechanisms of peripheral modulation of primary affer-

Traditionally, the main mechanism involved in development of chronic visceral pain is thought to be neuroinflammation. This pathway effects peripheral and central nerve sensitization and/or dysfunction of inhibitory descending pathways [3]. However, in clinical studies, visceral nociception strongly affects negative sensations that difficult to correlate with visceral traumata. Most nociceptive systems involved in peripheral sensitization originate in free sensory nerve endings of target organs that send their signals toward primary afferent

Visceral sensitization may develop as a result of interaction between the nervous and immune systems. All visceral afferents can be sensitized by proinflammatory mediators, such as serotonin, histamine, nitric oxide and ATP, leading to neuropathic hyperalgesia. During inflammation, mast cells and leukocytes secrete inflammatory mediators such as cytokines and prostaglandins that activate polymodal nociceptors triggering the response of normally silent mechano-insensitive receptors. Mast cell mediators can also activate vanilloid receptors

The serotonergic pathway, one of the main inhibitory mechanisms in the CNS, may also be functionally important in facilitating peripherally mediated visceral pain [4]. Most antidepressants gradually increase serotonin level in the brain. Indeed, depression has been reported to be associated with immunosuppression. Serotonin plays a major role in the gut-brain axis by

) and bradykinin (BK2) at PNS, causing hyperalgesia.


ent sensory neurons in development of chronic pelvic pain.

2 Neuroplasticity - Insights of Neural Reorganization

**2. Neuroplasticity in peripheral nervous system**

(TRPV1), purinergic (P2X<sup>3</sup>

sensory neurons within the lumbar-sacral regions of dorsal root ganglia (L1

The chronic pelvic pain (CPP) from pelvic structures is more prevalent in female subjects compared to males. In clinical studies, this sexual dimorphism is well recognized: the incidence of functional disorders is 2–3 times higher in women with IBS and even greater with IC/PBS. A large body of literature supports that concept indicating estrogen modulation of different nociceptive pathways [2]. In our previous studies, we found that estrogen receptors (ERα and ERβ) are present in small-to-medium size DRG neurons (presumably nociceptors) and ATP-sensitive DRG neurons respond to 17β-estradiol (E2 ) [7], which correlated well with the idea that visceral afferents are E2 sensitive. Our data clearly suggest that in addition to CNS actions, E2 can act in the periphery to modulate nociception [1]. Specifically, E2 acts in DRG neurons to modulate L-type VGCC and through group II metabotropic glutamate receptors [8]. One prominent way E2 modulates neuronal excitability is through the interaction with antinociceptive opioids such as enkephalins, β-endorphin and pronociceptive nociceptin/ orphanin. Furthermore, our hypothesis is that increased nociceptive input from an inflamed organ (i.e. uterus) sensitizes neurons that receive convergent input from an unaffected organ (i.e. colon). In summary, our data suggest that potential site of visceral cross-sensitivity is the dorsal root ganglion [9]. DRG neurons could be responsible for changes observed in the perception of pain during the etiology of different functional syndromes associated with pain.

Several lines of evidence indicate that E2 directly influences the functions of primary afferent neurons. Both estrogen receptors (ERα and ERβ) are present in DRG and visceral pain is affected by hormonal level in cycling females [1, 2]. Even a large body of literature supports the idea that E2 modulates nociceptive responses in pelvic pain syndromes, the exact mechanism remains unresolved. Within the context of our hypothesis, E2 modulation of nociceptive response depends on the type of pain, its durations and the involvement of other nociceptivemediated mechanisms.
