**3. Nociceptive system modulation in primary headaches**

Known in a great measure, the endogenous antinociceptive system is organized on three levels: first, supraspinal descending inhibition; second, segmental spinal inhibition (inhibitor complex of the pain in the posterior horn of the spine), and third, propriospinal, heteroseg‐ mental inhibition‐supraspinal descending inhibition system.

The experimental studies, using pharmacological techniques, inhibitors, electrical stimulators, and functional neuroimaging techniques, revealed the existence of a complex system of pain modulation, a real neuronal matrix that is highly activated at the arrival of a nociceptive stimulus. This network is a dynamic and plastic connection between different neuronal relays and it is also involved in other higher nervous activities: cognition, emotion, and motivation. The pain network, with an anatomical basis still partially known, involves a series of neuro‐ modulators and receptors and may be influenced both pharmacologically (including opiates, cannabinoids, NSAIDs, and serotonin/norepinephrine reuptake blockers) and mentally and emotionally, ultimately determining the sensation of pain [17].

Anatomically, the parietal cortex 1 and 2, insular lobe, thalamus, hypothalamus, amygdala, and the rostral anterior cingulate cortex (rACC) send messages to the periaqueductal gray matter (PAG) from where the descending inhibitor stimulus is transmitted to the trunk (sensory trigeminal core) and rostral bone marrow, with descending inhibitory projection on the medullar posterior horn.

The periaqueductal gray matter is a real center for holistic integration of the painful sensation because it has connections with the prefrontal cortex and amygdala, which, in turn, have a recognized role in the integration of emotions, anxiety, and risk assessment with avoidance [18].

Fields et al. [19] have identified in the rostral cervical region the existence of two neuronal populations with different functional roles: population "on" which increases its discharges before initiating the nociceptive reflex, and the population "off" which reduces its discharges when responding to the pain and whose activation produces analgesia. The population "on" is represented by the μ‐opioid receptors whose activation inhibits the discharges of these neurons. Opioids and cannabinoids inhibit pain by enhancing the baseline firing rate of "off"‐ cells and eliminating the "off"‐cells pause in response to nociceptive stimuli [20]. In these interdependent connections, a series of neuromediators may have multiple actions, such as serotonin and norepinephrine, but also other aminergic systems.

The PAG and RVM stimulation determine the release of serotonin, as the nucleus raphe magnus located near the trigeminal nucleus, in the bilateral inferior arch, releases serotonin with a possible role in the process of endogenous analgesia. The functional neuroimaging using BOLD technique revealed the activation of the nucleus as answer to the trigeminal painful stimulation suggesting its role [14, 21, 22].

Conversely, the implication of serotonin in stimulating the PAG and RVM neurons is not fully understood, but it is obvious that other nonserotonergic systems are involved in modulating the pain. Serotonin could be both inhibitory and facilitating the pain depending on the subtype of receptors excited. That GABAergic and glycinergic projections from the RVM mediate antinociception [23].

Norepinephrine released by the locus coeruleus and Kölliker‐Füse nuclei under the impulses arrived from PAG and RVM seem to have a strong antinociceptive role by blocking the pre‐ and postsynaptic receptors of the spinal neurons involved in transmitting the pain or by stimulating the alpha‐2‐adrenergic receptors and indirectly by stimulating the alpha‐1‐ receptors, which will cause the depolarization of inhibitory GABAergic neurons [23].

#### **3.1. Segmental spinal inhibition**

nucleus (DRt), the rostral ventral medulla (RVM), and the midbrain periaqueductal gray

The motor component of the cerebrovascular system implies an extrinsic innervation of the meningeal vessels, from the cervical (sympathetical), otic, sphenopalatin, and trigeminal ganglia (parasympathetical) and an intrinsic innervation for the small intraparenchimatous

Cerebral blood flow (CBF) is regulated by vasomotor, chemical, metabolic, and neurogenic mechanisms, but under normal physiological conditions neurogenic control has little influence

There is considerable experimental literature to document that stimulation of trigeminal

From the time of the stimulation of the nociceptive endings until the perception of the pain sensation, the transmission of the signal is modified by a series of mechanisms with the final

Known in a great measure, the endogenous antinociceptive system is organized on three levels: first, supraspinal descending inhibition; second, segmental spinal inhibition (inhibitor complex of the pain in the posterior horn of the spine), and third, propriospinal, heteroseg‐

The experimental studies, using pharmacological techniques, inhibitors, electrical stimulators, and functional neuroimaging techniques, revealed the existence of a complex system of pain modulation, a real neuronal matrix that is highly activated at the arrival of a nociceptive stimulus. This network is a dynamic and plastic connection between different neuronal relays and it is also involved in other higher nervous activities: cognition, emotion, and motivation. The pain network, with an anatomical basis still partially known, involves a series of neuro‐ modulators and receptors and may be influenced both pharmacologically (including opiates, cannabinoids, NSAIDs, and serotonin/norepinephrine reuptake blockers) and mentally and

Anatomically, the parietal cortex 1 and 2, insular lobe, thalamus, hypothalamus, amygdala, and the rostral anterior cingulate cortex (rACC) send messages to the periaqueductal gray matter (PAG) from where the descending inhibitor stimulus is transmitted to the trunk (sensory trigeminal core) and rostral bone marrow, with descending inhibitory projection on the

The periaqueductal gray matter is a real center for holistic integration of the painful sensation because it has connections with the prefrontal cortex and amygdala, which, in turn, have a recognized role in the integration of emotions, anxiety, and risk assessment

vessels, derived from brain stem nuclei such as locus coeruleus [15].

aim of improving the painful sensation.

48 Current Perspectives on Less-known Aspects of Headache

medullar posterior horn.

with avoidance [18].

on cerebral autoregulation as other methods of control are dominant [16].

**3. Nociceptive system modulation in primary headaches**

mental inhibition‐supraspinal descending inhibition system.

emotionally, ultimately determining the sensation of pain [17].

afferents can result in cranial autonomic outflow, the trigeminal–autonomic reflex.

(PAG) [12–14].

At the posterior horn of the spine, the endogenous antinociceptive system is represented by interneurons and the supramedullary descending endings. The opioids act on μ receptors located on the presynaptic endings of the related fibers where it blocks the calcium channels and open the potassium channels producing a hyperpolarization by inhibiting the release of neurotransmitter and thus analgesia. The endogenous analgesic system that is usually inactive and whose center is PAG projects from it axons (enkephalin conductors) to the raphe magnus nucleus, and from here to the interneurons from the posterior horn where they can secrete serotonin facilitating the release of enkephalins from the spinal interneurons. The interneurons receive external nociceptive fibers and the enkephalins from the two sources are blocking presynaptically the nociceptive signal. The stimulation of the opioid receptors from the related nociceptive fibers by enkephalin will determine the same blockage of the calcium channels whose activation is also necessary for releasing the substance P [24]. Supraspinal descending inhibition may not only depress mean discharge rates of nociceptive spinal dorsal horn neurons, but also may modify harmonic oscillations and nonlinear dynamics (dimensionality) of discharges [25].

#### **3.2. Propriospinal, heterosegmental inhibition**

Besides the classical, local, segmental, and supraspinal descending systems, it seems that there is a third endogenous antinociceptive system: propriospinal, intersegmental system inhibiting the nociceptive neurons in the dorsal horn. It seems to modulate partially the descending pathways and it is activated by conditioning (stimulating) the heterosegmental painful stimuli causing a neuronal constrastimulation (counterirritation) [25].

This multistage organization of the endogenous antinociceptive system can be influenced with beneficial results or it can be demodulated resulting in pain exacerbation.

The new functional neuroimaging techniques have showed the influence of the placebo‐type psychogenic factor that cause the activation of the descending inhibitory network with the stimulation of the μ‐opioids in rostral anterior cingulate cortex (rACC), the posterior cingulate cortex(PCC), the dorsolateral prefrontal cortex, and the anterior insular cortex with the increase of the blood flow in PAG also. Similarly, the reverse reaction of waiting, anticipation of a painful sensation determines a tendency to inhibition similar to that of an intense stimulation (nocebo effect) [26].

In patients with migraine, interictal, the functional MRI studies revealed an increase in the nociceptive diffuse activity mediated in different ways [27]. Another way of modulating pain is represented by "the nociceptive diffuse control of the pain." The concept, issued by Le Bars since the 8th decade of the last century refers to the wide dynamic range inhibition of neurons from the dorsal horn responsive to a painful stimulation by a nociceptive stimulus applied elsewhere in the body. The inhibition mechanism seems to be central and its loss is involved in the chronic painful syndromes, but also in the becoming chronic and of medication‐overuse headache [28, 29]. This system is integrated in the dorsal reticular nucleus which receives nociceptive information from the marrow and communicates with PAG and RVM, amygdala, thalamus, and finally inhibiting the marrow by descending projections. The neurons in dorsal reticular nucleus (DRt) establish connections with the cortex and multiple central nervous system areas involved in modulating the pain–the spino‐supraspinatus loop [30].

Perrotta et al. [31] found the existence of a process of central sensitizing of the pain pathways, with the abnormal and facilitating processing of the stimuli in the trigeminal nucleus both in crisis and interictally, suggesting a chronic hyperexcitability possibly conditioned genetically with dysfunctional consequences on the antinociceptive modulating system [32].

It is possible that this demodulation of the nociceptive stimulus processing to be due to a defect of the default mode network, claim supported by the neuroimaging morphofunctional studies which revealed metabolic changes in the brain areas involved in processing the pain. The default mode network consists of a series of relays (part of the medial temporal lobe, part of the medial prefrontal cortex, and the posterior cingulate cortex, along with the adjacent ventral precuneus and the medial, lateral, and inferior parietal cortex) whose anatomical bases are intertwined with the pain processing pathways. The current data suggest that the network is active when the individual is not focused on the outside world and the brain is at wakeful rest and it is possible that it participates in the basic settings of the main brain functions [33].

The hypothalamus, the vegetative brain, establish direct anatomical connections with the trigeminal structures and it is involved in a variety of cerebral functions with vegetative component including regulating the vasomotricity and processing of pain, maintaining the homeostasis. The recent studies have found that there is a disorder of its functional connectivity with the vegetative structures, in the sense of its increasing or decreasing, all being able to disorder the processing of exteroceptive stimuli, especially those painful [34–37].

**3.2. Propriospinal, heterosegmental inhibition**

50 Current Perspectives on Less-known Aspects of Headache

effect) [26].

causing a neuronal constrastimulation (counterirritation) [25].

beneficial results or it can be demodulated resulting in pain exacerbation.

Besides the classical, local, segmental, and supraspinal descending systems, it seems that there is a third endogenous antinociceptive system: propriospinal, intersegmental system inhibiting the nociceptive neurons in the dorsal horn. It seems to modulate partially the descending pathways and it is activated by conditioning (stimulating) the heterosegmental painful stimuli

This multistage organization of the endogenous antinociceptive system can be influenced with

The new functional neuroimaging techniques have showed the influence of the placebo‐type psychogenic factor that cause the activation of the descending inhibitory network with the stimulation of the μ‐opioids in rostral anterior cingulate cortex (rACC), the posterior cingulate cortex(PCC), the dorsolateral prefrontal cortex, and the anterior insular cortex with the increase of the blood flow in PAG also. Similarly, the reverse reaction of waiting, anticipation of a painful sensation determines a tendency to inhibition similar to that of an intense stimulation (nocebo

In patients with migraine, interictal, the functional MRI studies revealed an increase in the nociceptive diffuse activity mediated in different ways [27]. Another way of modulating pain is represented by "the nociceptive diffuse control of the pain." The concept, issued by Le Bars since the 8th decade of the last century refers to the wide dynamic range inhibition of neurons from the dorsal horn responsive to a painful stimulation by a nociceptive stimulus applied elsewhere in the body. The inhibition mechanism seems to be central and its loss is involved in the chronic painful syndromes, but also in the becoming chronic and of medication‐overuse headache [28, 29]. This system is integrated in the dorsal reticular nucleus which receives nociceptive information from the marrow and communicates with PAG and RVM, amygdala, thalamus, and finally inhibiting the marrow by descending projections. The neurons in dorsal reticular nucleus (DRt) establish connections with the cortex and multiple central nervous

system areas involved in modulating the pain–the spino‐supraspinatus loop [30].

with dysfunctional consequences on the antinociceptive modulating system [32].

Perrotta et al. [31] found the existence of a process of central sensitizing of the pain pathways, with the abnormal and facilitating processing of the stimuli in the trigeminal nucleus both in crisis and interictally, suggesting a chronic hyperexcitability possibly conditioned genetically

It is possible that this demodulation of the nociceptive stimulus processing to be due to a defect of the default mode network, claim supported by the neuroimaging morphofunctional studies which revealed metabolic changes in the brain areas involved in processing the pain. The default mode network consists of a series of relays (part of the medial temporal lobe, part of the medial prefrontal cortex, and the posterior cingulate cortex, along with the adjacent ventral precuneus and the medial, lateral, and inferior parietal cortex) whose anatomical bases are intertwined with the pain processing pathways. The current data suggest that the network is active when the individual is not focused on the outside world and the brain is at wakeful rest and it is possible that it participates in the basic settings of the main brain functions [33].

The hypothalamus is also connected with the sympathetic cerebral structures, such as the parahippocampal gyrus and cerebellar peduncle. The accentuation of connectivity with these centers, found in patients with migraine could prevail in the cortical answer to external nociceptive stimuli. The finding was made by BOLD neuroimaging studies, by increasing the activity in these structures both in sympathetic stimulation and at rest. Similarly, there have been found hyperexcitable connections (enhanced functional connectivity) with parasympa‐ thetic structures (temporal pole, superior temporal gyrus, and cerebellar lobules V and VI) ultimately determining a disorder of the processing of internal stimuli in patients with migraine, explaining some features of reaction of the patient to external stimuli [38].

Locus coeruleus, the largest noradrenergic nucleus in the brain is connected by anatomical structures with the hypothalamus, with which it establishes hyperfunctional connections. Involved in modulating the neuronal discharges from thalamus and prefrontal cortex as response to the nociceptive stimuli and in the inhibition of the nociceptive reflexes, it may have an important role in processing the pain in patients with migraine [39]. The caudate nucleus recently involved in processing the pain has also hyperfunctional connectivity with the hypothalamus suggesting an involvement in the chronobiology of migraine [40].

On the other hand, a decrease in the functional connectivity with various cerebral structures (cortical regions in the frontal and occipital regions) was found where hypofunctions were found. No one can say for now that hypothalamus plays in migraine a role similar to vascular face algies, but it certainly interferes with the processing of the pain and it is responsible for a part of the vegetative manifestations in the migraine and their relationship with the human psyche. The disorder could be due to the large amount of information received from the neurons of the spinal trigeminal nucleus, repeated activation during the attacks, and a phenomenon of central sensitizing of the hypothalamic and autonomic connections [41].

In addition to the fast synaptic transmission mediated by classic neurotransmitters, the extra synaptic transmission of chemical signals such as neuropeptides could act a key role for long‐ term effects following intense noxious stimulation. These extra synaptic peptides, among their intrinsic vascular activity, also increase the excitability of neurons in the dorsal horn and trigger the expression of the immediate‐early genes, thus changing the underlying chronicity of the pain.

The transmission of the nerve signal to the trigeminal neurons also involves the presence of some peptides with strong vasodilatory action of the cerebral vessels, the essential link in the pathogenesis of the primary cephalalgias. These peptides (calcitonin gene‐related peptide— CGRP, substance P (SP), and neurokinin A—NKA) are often secreted by the same neuron, in different quantities and combinations giving them a remarkable functional diversity. Calcito‐ nin gene‐related peptide is the most potent vasodilator transmitter identified in the cerebral circulation, and its action is endothelium independent and associated with an increase in vessel wall cyclic AMP [42–44].

Substance P is a nondecapeptide involved in nociceptive transmission. In many vascular beds, including the cerebral bed, substance P is a potent vasodilator and it also dilates both arteries and veins *in situ* [45]. Substance P can induce protein extravasation in the periphery and a similar response is seen in the dura with protein extravasation and mast cell degranulation [46]. Neurokinin A can relax cerebral vessels both *in vitro* and *in vivo*, although it is only one‐ tenth as potent as substance P [47]. Both substance P and NKA coexist in perivascular nerve fibers in peripheral and cerebral vessels [48].

It is possible that the antinociceptive system to be activated not only by direct stimulation, but also by disinhibition in PAG. By researching the expression of the protein c‐FOS in the activated neurons, patterns different from the neuronal activity in the structures involved in controlling analgesia were found. The existence of these patterns different from the neuronal discharge especially in the spine and finding a background noise have suggested the existence of a tonic activity of the most nociceptive neurons in the posterior horn of the marrow determined by the supraspinal continuous discharges of the endogenous antinociceptive system defining the hypothesis of "prophylactic antinociceptive system" [49].
