Introduction

Migraine is one of the most debilitating neurological disorders, characterized by recurrent headache attacks [1, 2]. The concept that migraine is a channelopathy has been substantiated by the fact that familial hemiplegic migraine types 1 and 3 are caused by mutations in the genes encoding the α1 subunit of the CaV2.1 P/Q-type voltage-gated Ca2+ channel (CACNA1A) [3] and the α1 subunit of the neuronal NaV1.1 voltage-gated Na+ channel (SCN1A) [4], respectively. Furthermore, genetic abnormalities of the two-pore-domain K+ channel, TRESK, have been shown to cause a familial form of migraine with aura. Unlike the CaV2.1 and NaV1.1 channels, the TRESK channel is strongly expressed in trigeminal ganglion (TG) neurons, pointing to the importance of peripheral trigeminal nociception in migraine pathophysiology. Transient receptor potential (TRP) channels are non-selective cation channels that transduce various noxious stimuli into pain signals [5]. They are expressed in TG neurons, and some are associated with the functions of calcitonin gene-related peptide (CGRP) [6, 7], a key target molecule of migraine therapy [8]. Considerable data support the role of TRP channels in migraine, so TRP channel modulation may be a promising therapeutic strategy for its treatment. In addition, migraine attacks are known to be provoked and worsened by environmental factors [1, 2]. TRP channels may also be involved in the trigger mechanism of attacks, because they sense changes in ambient temperature [9] and environmental pollutants [10]. Here, we discuss the roles of TRP channels in the pathophysiology of migraine and the potential of TRP-based approaches to migraine therapy.

Migraine Pathophysiology

Migraine, a chronic neurological disorder that affects > 10% of the general population [1, 2], is clinically characterized by recurrent attacks of moderate to severe headache lasting 4–72 h without treatment. Attacks are usually accompanied by nausea, vomiting, and heightened sensitivity to light and sound. The Global Burden of Disease study has recently identified migraine as the most disabling neurological disorder and the second leading cause of years lived with disability worldwide [11]. Its pathophysiological mechanisms involve both the central and peripheral nervous systems. In 25%–30% of patients, some attacks are accompanied by an aura phase, which manifests with transient visual, sensory, and language or brainstem disturbances [12]. The aura is now believed to be caused by cortical spreading depolarization/depression (CSD), a slowly propagating wave of rapid, near-complete depolarization of brain cells that lasts for about 1 min and silences electrical activity for several minutes [13]. Moreover, many patients experience prodromes such as fatigue and changes in appetite hours before an attack. Neuroimaging data show abnormal activation of the hypothalamus during prodromes [14, 15]. On the other hand, intravenous administration of CGRP has been shown to induce attacks specifically in migraine patients [16, 17]. CGRP does not readily permeate the blood-brain barrier, thus making it likely that the neuropeptide acts at peripheral sites, such as the TG, the dura mater, and meningeal vessels in this setting. This tenet is endorsed by the fact that monoclonal antibodies targeting CGRP or its receptor, which do not cross the blood-brain barrier either, are efficacious in the prophylaxis of attacks [8]. Hence, peripheral CGRP actions clearly play a crucial role in the development of migraine attacks.

It remains elusive how migraine headaches are generated. However, it has been postulated that the release of neuropeptides such as CGRP and substance P (SP) by trigeminal nerve fibers causes neurogenic inflammation and subsequent sensitization [18]. These alterations may be responsible for the relatively long and severe headaches associated with migraine. Furthermore, animal studies have demonstrated that CSD can generate a nociceptive stimulus capable of activating the trigeminal system [19,20,21], which would account for the temporal relation between the aura and the headache phases. Recent studies have clarified that CSD also induces dural macrophage activation, mast cell degranulation, and dilatation of the pial and dural vessels, all of which seem to be causes of headache [22, 23].

In particular, meningeal mast cells seem to be relevant in consideration of their proximity to the meningeal nociceptors and their ability to release a plethora of pro-inflammatory and pro-algesic substances [24]. Migraine symptoms are affected by environmental factors. In some patients, attacks are triggered by changes in ambient temperature or atmospheric pressure [9]. Moreover, migraine headaches are exacerbated by light [25], sound, and chemical irritants, such as cigarette smoke [10]. These observations highlight the role of the information detected by sensory neurons in migraine pathophysiology.

Involvement of TRP Channels in Migraine

The trp gene was originally discovered in a Drosophila mutant with defective vision [26]. Subsequently, this gene was found to encode a protein that plays an important role in phototransduction. Light-activated rhodopsin induces phospholipase C to hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP2) which leads to increased Ca2+ permeability of the TRP channel causing the depolarization of photoreceptor cells [27]. The ancestral TRP channel, which possesses six transmembrane domains, is regarded as an ion channel prototype that transduces environmental stimuli into Ca2+ signaling.

In 1997, Caterina et al. [28] isolated a cDNA clone encoding a capsaicin receptor with non-selective cation channel activity. This receptor was initially referred to as vanilloid receptor 1 (VR1) because a vanilloid moiety of capsaicin was an essential component responsible for the activation of this novel receptor. Concomitantly, it was revealed that VR1 was structurally related to the TRP channel family. Hence, VR1 was later renamed TRP cation channel V1 (TRPV1). From the functional viewpoint, the gating of TRPV1 is driven by noxious heat (> 42°C) which helps us understand why the sensation induced by capsaicin ingestion is perceived as “hot” and “burning”. With the subsequent increase in the number of mammalian TRP family members, they are now classified into six subfamilies – TRPC, TRPV, TRPM, TRPML, TRPP, and TRPA [29, 30]. Some of them were found to be activated by specific temperature ranges [31]. These thermosensitive TRP channels are expressed in primary sensory neurons, which include TG neurons, to confer the ability to detect changes in ambient temperature. Besides, most TRP channels serve in nociceptors as a transducer of noxious stimuli other than non-physiological temperature changes into pain signals [5]. TRPV1 is activated by protons [32, 33] and TRPA1 by reactive oxygen species (ROS) [34]. It should be pointed out that both of these substances have been implicated in the pathogenesis of various pain disorders including migraine [35]. Furthermore, TRP channels are known to be sensitized under pathological conditions. For example, the sensitization of TRPV1 to heat is responsible for the thermal hyperalgesia associated with carrageenan-induced inflammation [36].

Taken together, TRP channels are involved in the detection of environmental changes and trigeminal nociception. In migraine pathophysiology, where neurogenic inflammation is considered to play an important role [37], TRP channel activity is likely to be upregulated, so blocking such sensitization would be a potential therapeutic strategy. For these reasons, the relationship between TRP channels and migraine has attracted attention [30, 38, 39]. Tremendous amounts of data on mammalian TRP channels have been accumulated since the discovery of VR1/TRPV1. In this article, we focus on the roles of TRPV1, TRPA1, TRPM8, and TRPV4 in the pathophysiology of migraine, because relatively sufficient data relevant to migraine are available for these four channels (Fig. 1).

Fig. 1
figure 1

Major functions of TRPV1, TRPM8, TRPA1, and TRPV4 channels relevant to migraine pathophysiology. BoNT-A, botulinum neurotoxin type A; CSD, cortical spreading depression; NGF, nerve growth factor; PGE2, prostaglandin E2; ROS, reactive oxygen species; TRP, transient receptor potential.

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TRPV1

TRPV1 Localization and Function in the Trigeminal System

TRPV1 is expressed mainly in small- and medium-sized TG neurons [6, 40, 41]. Approximately 10%–20% of TG neurons are reported to be positive for TRPV1 with slight species differences [6, 40,41,42]. Moreover, a subset of TRPV1-positive neurons is known to contain CGRP [6, 41], and TRPV1 stimulation induces CGRP release [43,44,45]. The coexistence of TRPV1 and CGRP has also been confirmed in dural trigeminal fibers [6, 7]. The dura mater is considered to be an important disease locus of migraine [46]. Clinical features of attacks, such as a throbbing headache exacerbated by physical activity, nausea, and photophobia, have also been reported in patients with meningitis [46]. Sumatriptan, which is widely used in acute migraine therapy, was developed with success in animal studies using plasma protein extravasation and vasodilation in the dura mater as surrogate markers [37]. Although the exact role of TRPV1 in migraine pathogenesis remains obscure, the simplistic view that the headaches are caused by nociceptive stimuli to TRPV1-expressing nociceptors is not tenable, because the TRPV1 antagonist SB-705498 was not effective as an acute therapy in a clinical study [30, 47]. In the trigeminal nervous system, the CGRP receptor components calcitonin receptor-like receptor and receptor activity-modifying protein 1 are expressed in thinly-myelinated Aδ-fibers, whereas CGRP is present in unmyelinated C-fibers [48, 49]. This implies that C-fiber-derived CGRP would act on CGRP receptors located on Aδ-fibers. CGRP itself does not directly cause migraine; rather it induces migraine attacks in a delayed manner [16, 17]. Several lines of evidence show that CGRP is involved in sensitization [50,51,52,53]. CGRP-induced sensitization is known to play a role in the potentiation of N-methyl-D-aspartic acid receptor functions through protein kinase A-mediated phosphorylation [54,55,56,57]. Both CGRP and glutamate are increased in the cerebrospinal fluid from patients with chronic migraine [58]. Thus, it has speculated that TRPV1 contributes to trigeminal sensitization by promoting the release of CGRP from C-fibers (Fig. 2). This paradigm would be compatible with the failure of TRPV1 blockade to abort migraine attacks because TRPV1 activation is positioned as an upstream event in the development of attacks. Consequently, TRPV1 inhibition after an attack had begun would be too late to relieve the headache.

Fig. 2
figure 2

Possible action of TRPV1 on CGRP release from trigeminal terminals. TRPV1 activation (1) leads to CGRP release from C-fibers (2). Subsequently, CGRP acts on the CGRP receptor expressed on the surface of Aδ-fibers (3), resulting in the development of sensitization (4). Such sensitization of the trigeminal system may be responsible for the generation of the headache. CGRP, calcitonin gene-related peptide.

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CSD and TRPV1 Functions

CSD is known to activate the MAP kinase extracellular signal-regulated kinase (ERK) in TG neurons [21]. Since this activation is disrupted by the TRPV1 inhibitor capsazepine, TRPV1 is likely to be activated by CSD [21]. TRPV1 is known to be expressed in those central nervous system regions relevant to migraine pathophysiology, such as the hippocampus, basal ganglia, thalamus, and hypothalamus [59]. Mechanically-induced CSD is not inhibited by TRPV1 blockade with A-993610, implying that TRPV1 activity does not play a significant role in the process of eliciting CSD [60]. However, repetitive capsaicin stimulation of the trigeminal region has been shown to lower the threshold of CSD induction by suppressing GABAergic activity [61]. It is inferred that repeated trigeminal nociceptive stimulation renders the cerebral cortex susceptible to CSD induction. An important clinical implication of this finding is that clustering of migraine aura attacks may increase the likelihood of recurrence.

Therapeutic Strategies in Migraine with Regard to TRPV1 Functions

TRPV1 functions are known to be modified by inflammatory mediators. Prostaglandin E2 sensitizes TRPV1 channels through protein kinase A-induced phosphorylation of the scaffold protein named A-kinase anchoring protein 150 [62]. Bradykinin enhances TRPV1-mediated currents in a protein kinase C-dependent manner [63]. complete Freund’s adjuvant promotes the translocation of TRPV1 to the cell surface via cyclin-dependent kinase 5-mediated TRPV1 phosphorylation at threonine 407 [64] and increases TRPV1 channel activity via small ubiquitin-like modifier (SUMO)ylation at lysine 822 [65]. Although nerve growth factor (NGF) promotes neuronal growth during development, it also serves as an inflammatory mediator with pro-algesic actions [66]. Of particular relevance, NGF is increased in the plasma and cerebrospinal fluid of patients experiencing chronic daily headaches [67]. NGF increases TRPV1 expression by activating p38 MAP kinase [68], which is mediated by the ubiquitin ligase MYCBP2 [69]. Furthermore, ligation of NGF to the TrkA receptor leads to TRPV1 phosphorylation at tyrosine 200 via Src kinase, causing increased insertion of TRPV1 into the plasma membrane [70]. Toll-like receptors (TLRs) are involved in innate immunity [71, 72], and TLR4 coexists with TRPV1 in TG neurons [73]. Recent evidence has shown that TLR4 inhibits the endocytosis of TRPV1, thus increasing its cell-surface expression level [74]. Collectively, in migraine management, anti-inflammatory measures would be favorable for restricting TRPV1 activity.

Botulinum neurotoxin type A (BoNT-A) is used to treat chronic migraine. Electrophysiological analyses have revealed that BoNT-A selectively inhibits the C-fibers of meningeal nociceptors [75]. There is anatomical evidence for meningeal nociceptors that send collaterals to the scalp, which provides a rationale for the ability of subcutaneously injected BoNT-A to affect dural trigeminal functions [76,77,78]. Furthermore, TRPV1 and TRPA1 functions are blocked by BoNT-A [79]. In agreement with these findings, BoNT-A decreases TRPV1 expression in the TG and trigeminal nerve fibers, while P2X3 expression is unaffected [80]. BoNT-A-treated mice are less responsive to capsaicin [80] and in primary cultures of TG neurons, TRPV1 cell-surface expression levels are reduced by BoNT-A treatment. Site-directed mutagenesis of TRPV1 at tyrosine 200 leads to a remarkable decrease in its expression, and this effect is reversed by proteasome inhibition. The last finding raises the possibility that TRPV1 that cannot be normally inserted into the plasma membrane is degraded by the cytoplasmic proteasome system (Fig. 3). The TRPV1 antagonist SB-705498 was not only abandoned as an acute anti-migraine therapy, but hyperthermia was found to be its unfavorable side-effect [30, 47]. By contrast, BoNT-A-mediated TRPV1 inhibition has the major advantage of not causing hyperthermia.

Fig. 3
figure 3

Impaired sorting of TRPV1 to the plasma membrane reduces the TRPV1 expression level. A Normally, TRPV1 is translocated to the plasma membrane via exocytosis. B BoNT-A inhibits the exocytosis-mediated sorting of TRPV1 to the plasma membrane. TRPV1 proteins that reside in the cytoplasm are subjected to proteolysis by the proteasome system, leading to reduced expression of TRPV1. BoNT-A, botulinum neurotoxin type A.

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TRPM8

TRPM8 as a Cold Sensor

TRPM8 was discovered as a non-selective cation channel responsive to cold (8°C–25°C) and menthol [81, 82]. Regarding its activation, there is an interaction between these stimuli, such that exposure to menthol elevates the threshold temperature for cold stimulation [81, 82]. Intriguingly, PIP2, which negatively regulates TRPV1 functions, conversely enhances TRPM8 activity. Hence, phospholipase C activation following TRPM8 stimulation downregulates TRPM8 functions, thus causing rapid desensitization [83,84,85]. Genetic ablation studies have corroborated that TRPM8 plays a crucial role in cold sensation [86, 87]. Unlike TRPV1, TRPM8 expression is restricted to primary sensory neurons in the nervous system [82]. In the TG, TRPM8 is mainly expressed in small neurons [78, 88, 89].

Functional Roles of TRPM8 in Pain Disorders and Migraine

TRPM8 seems to have dual implications for pain; it is involved in the development of cold allodynia, whereas cold stimulation in the temperature range that activates TRPM8 provides innocuous and soothing sensations. Nerve injury-associated and complete Freund’s adjuvant-induced cold allodynia is attenuated in TRPM8-knockout mice [87]. In accord with this, there is a movement for therapeutic application of TRPM8 antagonists to pain disorders [90]. On the other hand, TRPM8 has been found to mediate the analgesic effects of moderate cooling against the painful stimulus induced by formalin administration [86]. From the clinical viewpoint, menthol application can relieve migraine headaches [91, 92]. It has been pointed out that menthol has differing effects on capsaicin-induced pain depending on the time between exposure to capsaicin and menthol [93]. Hence, it is inferred that TRPM8 is involved in either sensing unpleasant cold stimuli or mediating the effects of cold analgesia in a context-dependent manner. Since its discovery, TRPM8 has been found to be co-expressed with TRPV1 in a subset of TG neurons [81]. Although the significance of this coexistence remains to be fully elucidated, TG neurons co-expressing TRPM8 and TRPV1 may be involved in eliciting noxious pain [94]. The co-expression frequency of TRPV1 and TRPM8 in TG neurons is increased in inflammatory soup-induced meningeal inflammation [78]. While this may favor the occurrence of cold allodynia, the increased coexistence concomitantly provides a greater chance for the ability of TRPM8 stimulation to antagonize TRPV1 functions (Fig. 4). In support of the latter, TRPM8 activation with icilin alleviates thermal allodynia in inflammatory soup-induced meningeal inflammation [78], reminiscent of the efficacy of menthol in acute migraine attacks as noted above [91, 92].

Fig. 4
figure 4

Altered actions of TRPM8 in different situations. A TRPM8 activation in TG neurons exclusively expressing TRPM8 channels is believed to generate only innocuous sensations. B TRPM8 activation of TG neurons expressing both TRPV1 and TRPM8 causes noxious sensations. C When TRPV1/TRPM8-expressing TG neurons are subjected to TRPV1 activation in the dura, TRPM8 activation in their extracranial collateral axons can exert an analgesic effect, thus assuaging pain.

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TRPM8 Gene Polymorphism Determines the Susceptibility to Migraine Development

The relationship between TRPM8 and migraine has been attracting particular attention because genome-wide association studies have reproducibly shown that single nucleotide polymorphisms of the TRPM8 gene (rs10166942[C/T] and rs17862920[T/C]) determine an increased risk of migraine [95,96,97]. TRPM8 mRNA expression from the chromosome harboring rs10166942[C] was found to be lower than that derived from the chromosome harboring rs10166942[T] in dorsal root ganglion samples, and rs10166942[C] carriers are significantly less sensitive to cold pain than non-carriers [98]. Although the exact mechanism of this allelic expression imbalance is unclear, impaired transcription and/or transcript instability might be involved. Intriguingly, TRPM8 channels are subject to a variety of post-transcriptional modifications [99]. Epidemiologically, rs10166942[T] carriers are associated with reduced migraine risk compared to rs10166942[C] carriers. Hence, increased TRPM8 activity seems to favor the risk of developing migraine. This is consistent with preclinical findings in rats showing that icilin applied to the dura results in cutaneous allodynia [100]. Furthermore, migraine patients carrying rs10166942[T] are more likely to have chronic migraine and allodynic symptoms [101] indicating that TRPM8-related single nucleotide polymorphisms can affect the clinical phenotypes of migraine as well.

TRPA1

TRPA1 as a Polymodal TRP Cation Channel

TRPA1 (also known as ANKTM1), the sole member of the TRPA subfamily, was cloned from cultured human fetal lung fibroblasts [102]. TRPA1 is co-expressed with TRPV1 in a subpopulation of non-myelinated or thinly myelinated C- or Aδ-fiber neurons in the dorsal root ganglion, TG, and vagus ganglion [103]. TRPA1 expression has been identified in both peptidergic sensory neurons (enriched in CGRP, SP, and neurokinin A) and non-peptidergic, IB4-binding neurons [104]. There is direct evidence for the involvement of TRPA1 in pain disorders. A gain-of-function mutation in TRPA1 (p.Asp855Cys) has been identified as the cause of familial episodic pain syndrome characterized by recurrent episodes of debilitating upper body pain, triggered or exacerbated by fatigue, cold exposure, fasting, and weather changes [105]. TRPA1 was originally identified as a noxious cold-sensitive cation channel activated by temperatures below 16°C [106]. In addition, TRPA1 is sensitive to pungent food ingredients (e.g., allyl isothiocyanate [mustard oil], cinnamaldehyde [cinnamon], allicin [garlic], and eugenol [clove bud oil compounds]), environmental irritants, and industrial pollutants, as well as endogenous substances (e.g., bradykinin, ROS, nitric oxide [NO], and lipid oxidation products) [107, 108], some of which are known to trigger migraine attacks.

Is TRPA1 a Crucial Molecule for Migraine Headache Generation?

A growing number of studies have implicated TRPA1 in the development of migraine headache [109], and this is supported by the finding from the “headache tree”. It has long been known that exposure to Umbellularia californica, a tree native to southwestern Oregon and northern California, causes headache crises. Umbellulone, the major volatile component of its leaves, was found to increase the intracellular Ca2+ concentration in TRPA1-transfected HEK293 cells in a concentration-dependent manner, and umbellulone-evoked currents in mouse TG neurons were abrogated by TRPA1 knockout [110]. These findings indicate that umbellulone is a TRPA1 agonist. Furthermore, umbellulone administration evokes CGRP release from TG neurons and dural trigeminal nerves, increases meningeal blood flow [110], and facilitates CSD propagation [111]. Regarding the involvement of TRPA1 in CSD induction, a recent study using brain slices demonstrated that local ROS application (H2O2) promotes cortical responsiveness to CSD in a way that involves TRPA1 and CGRP [112]. Consistent with this, cortical neurons have been shown to express TRPA1 [112, 113] and CGRP [114]. However, in this paradigm, it is unclear how ROS is generated within the cerebral cortex at the initial step. Another possible scenario for the involvement of these three key players in determining CSD susceptibility might be that CSD stimulates meningeal nociceptors [20], thereby causing TRPA1/TRPV1 activation [21], CGRP release, and neurogenic inflammation in the dura mater [22, 23], thus lowering the threshold for CSD induction [61]. In this model, it is envisioned that ROS production in meningeal nociceptors is induced by CSD [115] and/or TRPV1 activation [116], where TRPV1-generated ROS might be able to activate TRPA1 in an autocrine and/or paracrine manner. The involvement of ROS-induced TRPA1 activation has also been reported in a trigeminal neuropathic pain model, where chemokine (C-C motif) ligand 2-medated mobilization of macrophages/monocytes plays a pivotal role [117]. Moreover, it has been shown that ROS production downstream of TRPA1 activation in Schwann cells may contribute to the development of neuropathic pain [118].

TRPA1 and Environmental Migraine Triggers

In addition, some substances cause headaches in susceptible individuals. Acrolein is known to be a major irritant in cigarette smoke and an established migraine trigger [10]. The intranasal application of acrolein also evokes CGRP-dependent meningeal vasodilation via TRPA1 activation [119]. Furthermore, acrolein exposure produces chronic migraine phenotypes, such as peri-orbital allodynia, c-Fos induction in the trigeminal nucleus caudalis, and altered behavior in rats [120]. Therapeutically, the acrolein-induced increase in meningeal blood flow is attenuated by sumatriptan and valproic acid [120], the latter of which is known to be a prophylactic drug for migraine [121]. Hence, these anti-migraine drugs seem to exert an inhibitory action on TRPA1 itself or its downstream events.

Migraine attacks are provoked by NO donors, such as nitroglycerin and glyceryl trinitrate [122]. Glyceryl trinitrate has been reported to cause facial allodynia by inducing the TRPA1-mediated generation of reactive oxygen and carbonyl species within the TG [123]. Furthermore, endogenous NO and hydrogen sulfide contribute to CGRP release by activating TRPA1 in sensory nerves [108], which promotes nociceptive firing in the primary afferents underlying migraine pain under neuroinflammatory conditions [124].

TRPA1 as a Therapeutic Target of Migraine

Intriguingly, a number of anti-migraine drugs have been shown to desensitize or inhibit TRPA1 activity [108]. In particular, isopetasin (a major constituent of butterbur extracts) is reported to desensitize TRPA1, which may account for the anti-migraine action of butterburs [125]. Caffeine has been demonstrated to suppress human TRPA1 channels by an unknown mechanism [126]. Paracetamol (acetaminophen) has been demonstrated to exert an anti-nociceptive effect by desensitizing TRPA1 [127, 128]. Lastly, extracranial administration of BoNT-A inhibits meningeal nociceptors by reducing the expression of TRPA1 as well as TRPV1 [79]. However, it should be noted that it takes 7 days for BoNT-A to reduce the cell-surface expression of TRPV1 and TRPA1 in the dural nerve endings of meningeal nociceptors [79, 80]. Hence, the development of BoNT-like drugs with a more rapid onset of action is awaited.

TRPV4

TRPV4 is a Unique Polymodal TRP Cation Channel Discovered as an Osmotic Sensor

TRPV4 (also called VR-OAC [vanilloid receptor-related osmotically activated ion channel], VRL-2 [vanilloid receptor-like channel 2], TRPL2 [transient receptor-like channel 2], and OTRPC4 [osmosensory protein 9-like TRP channel, member 4]) was originally cloned as the vanilloid receptor-related channel activated by osmotic changes; it is strongly expressed in the kidney, liver, and heart [129, 130]. TRPV4 is a mammalian homolog of OSM-9 in Caenorhabditis elegans [130,131,132,133], and TRPV4 expression has been found to restore the osmotic avoidance response in OSM-9-deficient worms [134]. TRPV4 is now known to play an evolutionarily-conserved role in the transduction of osmotic and mechanical stimuli [29, 135, 136].

TRPV4 is a polymodal receptor with pleiotropic functions and widespread expression in various cell types/tissues throughout the body [103, 137]. It can be activated by various stimuli including physical factors (altered osmolarity, moderate heat [27°C–34°C] and mechanical stimuli such as membrane stretch and shear stress), chemical factors (endocannabinoids, arachidonic acid and its metabolites, and 4α-phorbol esters), and protons [103, 138,139,140,141].

Function and Localization of TRPV4 in Relation to Pain Disorders

TRPV4 is also involved in a plethora of pain conditions [29], encompassing mechanically-evoked [132, 142], inflammatory [143], neuropathic [144], visceral [145], and trigeminal pain conditions [146, 147]. Moreover, ultraviolet B-induced TRPV4 activation in the epidermis may be responsible for the development of sunburn pain [148]. A recent study has disclosed that the Piezo1–TRPV4 axis is involved in the exacerbation of pancreatitis via sustained elevation of intracellular Ca2+, thus highlighting the role of TRPV4 in visceral pain [149]. TRPV4 activation is known to potentiate the tetrodotoxin-sensitive Na+ current [150] and TRPV1 function [151] in TG neurons. Thus, TRPV4 also seems to serve as a pain enhancer in TG neurons.

TRPV4 expression has been reported not only in primary sensory neurons [147, 152] but also in satellite glial cells [153]. TRPV4 expression has also been recognized in the central nervous system [154]. TRPV4 mRNA has been found in neurons [132, 155], astrocytes [156], and microglia [157]. Astroglial TRPV4 has been shown to mediate brain edema after traumatic injury [158], a condition frequently encountered in familial hemiplegic migraine [159].

Emerging Evidence for the Importance of TRPV4 as a Novel Therapeutic Target for Migraine

Evidence for the role of TRPV4 in migraine pathophysiology is still scarce. However, its activation in response to mechanical stress and osmolarity changes fits into several aspects of migraine. For example, TRPV4 sensitization may be responsible for the worsening of migraine headaches by routine physical activity [160]. Also, trigeminal afferents are known to be sensitized by dural application of solutions with either increased or decreased osmolarity [161, 162]. In agreement with this, in vivo electrophysiological patch-clamp recordings demonstrated TRPV4-like currents in dural afferents in response to the application of hypotonic solutions and the TRPV4 activator 4α-PDD [163]. Furthermore, activation of TRPV4 within the dura of freely-moving animals induces migraine-like behaviors (cephalic and extracephalic allodynia) that are inhibited by a TRPV4 antagonist [163]. Formalin injection into the whisker pad has been found to induce trigeminal nocifensive behavior by activating Ca2+ entry through TRPV4 [147]. Mechanistically, concomitant exposure to formalin and high humidity seems to activate the TRPV4–p38 MAP kinase pathway [164].

In rat sensory neurons, immunoreactive TRPV4 is co-expressed with protease-activated receptor 2 (PAR2), SP, and CGRP, all of which are associated with migraine pathophysiology [165]. In particular, PAR2 activation in the meninges has been found to cause migraine-like pain behaviors [166]. Since PAR2 is known to underpin sustained activation of TRPV4 [167], a vicious cycle can be formed between these two molecules. Hence, the involvement of the PAR2–TRPV4 pathway in migraine pathophysiology may warrant further investigations.

Collectively, these findings raise the possibility that TRPV4 blockade can be a promising novel therapeutic strategy against migraines. A novel small molecule dual-channel inhibitor of TRPV4 and TRPA1 has been developed for attenuation of inflammation and pain including trigeminal irritant pain [143, 168].

Concluding Remarks

We reviewed the possible roles of four thermosensitive TRP channels in the pathophysiology of migraine. It is apparent that each of these channels operates as a detector of specific noxious stimuli. As discussed in this article, numerous preclinical and clinical data are available that support their various roles in migraine. The efficacy of BoNT-A in the management of chronic migraine implies that TRPV1 and TRPA1 are bona fide therapeutic targets of migraine. Notwithstanding, there is no definite proof that TRP channels mediate migraine headaches because TRP channel blockade has never been successful as a migraine therapy. Considering that migraine is a paroxysmal disorder, it is necessary to develop TRP antagonists with a rapid onset of action. Concomitantly, they should not have any adverse effect on body temperature in terms of clinical application. A better understanding of the relationship between TRP channels and CGRP, as well as adequate control of inflammatory conditions, may be key to maximizing the effectiveness of TRP channel-based anti-migraine therapies. Furthermore, TRP channel overactivity can profoundly affect cellular functions, for example, via mitochondrial toxicity [169, 170]. Hence, proper management of TRP channel activity would be protective against neuropathic changes.