*4.1. TRPV1 as a Crucial Migraine Initiator*

The first hint that TRPV1 is involved in migraine was demonstration of its co-expression with CGRP in rat TG neurons [134,135] and mouse dural afferent neurons [136], suggesting a crucial role for TRPV1 in migraine. Moreover, in rat dura mater, application of capsaicin is accompanied by vasodilatation mediated by CGRP release from sensory afferent nerves [112]. Another substantial link between migraine and TRPV1 was the demonstration that a frequent migraine trigger, ethanol, induced neurogenic vasodilation via TRPV1 activation and subsequent CGRP release in the TGVS of guinea pigs [118]. Although the triggering event that actually initiates a migraine attack remains elusive, Meents et al., proposed that the premonitory aura exhibited by some migraineurs promotes endogenous activation of TRPV1 [137]. Aura arises from a phenomenon called cortical spreading depression (CSD), a short-lasting depolarization of cortical neurons that is known to increase extracellular concentrations of H+, which can ultimately activate TRPV1 and induce CGRP release [119]. However, not all migraineurs experience aura, indicating that other endogenous mechanisms likely contribute to TRPV1 activation within the dura. Hence, although TRPV1 is currently recognized as a key player in migraine initiation, it is also likely involved in other phases and characteristics of migraine.

Sensitization of peripheral and central trigeminovascular neurons is usually observed following migraine attack onset. Peripheral sensitization mediates the throbbing perception of a headache, whereas sensitization of second-order neurons from the spinal trigeminal nucleus mediates cephalic allodynia and muscle tenderness [138]. Sensitization of TG neurons may contribute to direct sensitization of TRPV1, either by its increased activity or translocation to the cell membrane, or by increased protein production. Interestingly, the cerebrospinal fluid of chronic migraineurs (i.e., patients who have more than 15 migraine attacks per month) exhibit elevated levels of inflammatory mediators, including NGF [139]. Bradykinin and prostaglandin E2 are inflammatory mediators also released during neurogenic inflammation, and are commonly used in an animal model of headache to induce a chronic state of trigeminal hypersensitivity [113–115]. As already noted, NGF can trigger TRPV1 translocation to the plasma membrane, while bradykinin and prostaglandin E2 can orchestrate TRPV1 phosphorylation, which lowers its activation threshold. Moreover, TRPV1 expression is up-regulated in nerve fibers that innervate arteries in the scalp of chronic migraine patients [116]. Therefore, neurogenic inflammation that occurs during migraine attacks likely contributes to sensitization by modulating TRPV1 channel activity and expression.

Schwedt and colleagues proposed an interesting idea, namely that a state of persistent sensitization is maintained in migraineurs that enable more ready firing of TGVS [117]. They hypothesized that a cyclical process of migraine headaches causes interictal sensitization that contributes to predisposition to future migraine attacks. In their study, episodic and chronic migraineurs displayed enhanced sensitivity to thermal stimulation (decreased heat and cold pain threshold and tolerance) during the interictal period, compared with non-migraine controls. Such sensitization can partly be attributed to TRPV1 and may also explain why migraine patients do not tolerate ambient temperature changes [140]. In the same manner, a recent study showed that migraine patients exhibit enhanced extracephalic capsaicin-induced pain sensation during interictal periods, supporting the contribution of TRPV1 to interictal sensitization [141].

Another characteristic of migraines is their difference in prevalence and perception between men and women. Women are three-times more likely to suffer from migraine than men, and women experience more frequent, longer-lasting, and more intense migraine attacks than men [142]. Higher estrogen levels may in part be responsible for these differences. Interestingly, estrogen was recently shown to increase pain sensation by up-regulating expression of TRPV1 and ANO1 in TG neurons from female rats [97]. This could explain why women exhibit a higher susceptibility to migraine, and suggests that potential interaction of TRPV1 and ANO1 in TG neurons may be involved in migraine initiation.

Obesity has also been linked to migraine prevalence since it increases the risk of developing a migraine. Further persons with obesity suffer from more frequent and severe headache attacks [143]. A study involving mice fed a high-fat diet showed that facial intradermal injection of lower capsaicin doses are needed to induce photophobic behavior in obese mice compared to non-obese control mice [120]. Also, cell size distribution among TRPV1-positive cultured TG neurons from obese mice shifted towards larger cell diameters compared with control mice, and a higher capsaicin-induced calcium influx was observed in these neurons. In another mouse model that induced obesity through feeding of a high-fat and high-sucrose diet, dural application of capsaicin induced enhanced vasodilatory and vasoconstrictor responses compared with control animals. Basal and capsaicin-induced CGRP release from meningeal afferents was also increased [144]. These findings may explain why diet-induced obesity is associated with TGVS sensitization, which might occur via TRPV1 modulation, although the precise molecular mechanism is unclear.
