- Open Access
Role of ATP in migraine mechanisms: focus on P2X3 receptors
The Journal of Headache and Pain volume 24, Article number: 1 (2023)
Migraine is a major health burden worldwide with complex pathophysiology and multifarious underlying mechanisms. One poorly understood issue concerns the early steps in the generation of migraine pain. To elucidate the basic process of migraine pain further, it seems useful to consider key molecular players that may operate synergistically to evoke headache. While the neuropeptide CGRP is an important contributor, we propose that extracellular ATP (that generally plays a powerful nociceptive role) is also a major component of migraine headache, acting in concert with CGRP to stimulate trigeminal nociceptive neurons. The aim of the present focused review is to highlight the role of ATP activating its P2X3 membrane receptors selectively expressed by sensory neurons including their nerve fiber terminals in the meninges. Specifically, we present data on the homeostasis of ATP and related purines in the trigeminovascular system and in the CNS; the basic properties of ATP signalling at peripheral and central nerve terminals; the characteristics of P2X3 and related receptors in trigeminal neurons; the critical speed and persistence of P2X3 receptor activity; their cohabitation at the so-called meningeal neuro-immune synapse; the identity of certain endogenous agents cooperating with ATP to induce neuronal sensitization in the trigeminal sensory system; the role of P2X3 receptors in familial type migraine; the current state of P2X3 receptor antagonists and their pharmacological perspectives in migraine. It is proposed that the unique kinetic properties of P2X3 receptors activated by ATP offer an interesting translational value to stimulate future studies for innovative treatments of migraine pain.
The pathogenesis of migraine is complex since it involves interaction between peripheral and central neuronal mechanisms as highlighted in recent reviews [1,2,3]. One unresolved issue is the origin (and mechanism) of the typical pulsatile migraine pain, which is likely based on the activation of the meningeal trigeminovascular system [4,5,6]. To generate nociceptive signalling, which is further transmitted to the spinal cord/brainstem and to the higher pain centers, the trigeminal nerve terminals in the meninges should be first depolarized to a threshold sufficient to generate spiking activity . To date, a lot of depolarizing stimuli were proposed to trigger such a depolarization  including extracellular ATP, serotonin, endovanilloids, low extracellular pH, mechanical forces and/or changes in the ambient temperature [7, 9, 10]. In addition to produce nociceptive firing, depolarization of meningeal peptidergic C-fibers can release calcitonin gene-related peptide (CGRP), which nowadays is considered a principal contributor to migraine attacks and an important target for migraine treatment [11,12,13]. The mode of action of CGRP is multifarious because it comprises activation of immune cells, control of meningeal vessels and facilitation of trigeminal afferent activity [6, 12, 14]. In particular, one key mechanism of CGRP action is sensitization of nociceptive trigeminal ganglion neurons that become hyper-responsive to various stimuli . A major component of this phenomenon could be a strong upregulation of ATP-gated P2X3 receptors of trigeminal sensory neurons  and is one issue discussed in the present review.
While intracellular ATP is a purine compound essential for cell energy metabolism, extracellular ATP plays the role of neuromodulator/transmitter and is a potent pain-inducing agent [17,18,19]. Extracellular ATP acts on different subtypes of widely expressed ionotropic P2X and metabotropic P2Y receptors . Among them, P2X2 and P2X3 subtypes expressed in sensory neurons can mediate local depolarization of nerve terminals and initiate propagating nociceptive signalling [21,22,23]. The purinergic hypothesis of migraine originally suggested by Burnstock had considered a vascular target for the ATP action [24, 25]. Later studies have shown that ATP can directly activate meningeal afferents [26,27,28] supporting the role of an ATP neuronal mechanism in migraine headache. Furthermore, because ATP is also released by glial cells and by neurons alone [29, 30] or together with other transmitters , its activity may be extended to key regions of the CNS implicated in migraine.
The current focused review, drawn from our research carried out with in vitro preparations of trigeminal ganglia and meningeal tissue, discusses the trigeminal sensory mechanisms likely underlying the algesic action of ATP and the potential role of P2X3 receptors (widely expressed by such neurons ) in migraine pathophysiology. Thus, the present data should be considered euristically to stimulate further research in vivo on this subject and any translational value to the clinic.
Synthesis, release and degradation of ATP in migraine relevant tissues
Intracellular concentration of ATP is in the range of mM , while even higher levels of ATP can be found in synaptic vesicles as ATP is the co-transmitter released together with principal transmitters such as glutamate, noradrenaline, acetylcholine and GABA .
Apart from neuronal vesicular release, ATP can also be released from immune, vascular and glial cells or neurons through pannexin channels activated by mechanical forces or activation of specific receptors [34,35,36]. Pannexin-1 channels are functionally coupled with ATP-gated P2X7 receptors in the trigeminal ganglion . Enhanced ATP release can also occur due to mechanical stimuli mediated by mechanosensitive Piezo channels expressed by neuronal and non-neuronal cells . Indeed, it has recently been shown that Piezo1 channels of endothelial cells can provide flow-induced ATP release . Moreover, Piezo1 channels are expressed in trigeminal neurons [39, 40] and it has been hypothesized they react to pulsatile blood flow by triggering spiking activity during a migraine attack . It is tempting to speculate that direct mechanical activation of Piezo1 channels by pulsating vessels and ATP-dependent depolarization of meningeal afferents represent the basic mechanism of pulsatile migraine pain [39,40,41,42].
Extracellular ATP is very unstable and can provide only a short-lasting action as it is quickly broken down in living tissues by ectoenzymes  (Fig. 1). In addition to ATP breakdown to AMP by ecto-nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39), there are also other recently emerged extracellular enzymes (NTPDases2,3,8) including ATP-diphosphohydrolase, which can dephosphorylate ATP to the P2Y agonist ADP and the latter to the almost inactive AMP. The subsequent important step in this cascade is the degradation of AMP to physiologically active adenosine (ADO) by ecto-5'-nucleotidase/CD73  (Fig. 1).
Production of ADP at the first step of ATP hydrolysis can activate ADP-preferring metabotropic P2Y1, P2Y12 and P2Y13 receptors, which are expressed in trigeminal neurons and in glial cells and can modulate nociception . Interestingly, ADP can also provide an inhibitory effect on pro-nociceptive P2X3 receptors in sensory neurons  (Fig. 1). Unlike ATP, ADP does not excite meningeal afferents  and likely serves as negative feedback for ATP driven trigeminal nociception triggered by ionotropic receptors. This mechanism would originate from the local expression of ADP produced by NTPDases2,3,8 rather than by NTPDase1 mediated transformation of ATP to adenosine.
Adenosine can play either an anti-nociceptive role, via inhibitory A1 receptors widely expressed in neurons, or a pain triggering effect via activation of the cAMP-coupled A2a receptor subtype (Fig. 1). The latter operates via cAMP signalling to sensitize trigeminal neurons [45,46,47]. The modulatory action of ATP breakdown metabolites (ADP or adenosine) is expected to be most efficient because of the colocalization of specific NTPDases with the key components of the meningeal trigeminal nociceptive system such as vessels and nerves fibers. Our recently proposed approach, based on the detection of extracellular phosphate after ATP hydrolysis , has revealed ‘hot spots’ of intense ATP release/degradation around meningeal vessels surrounded by perivascular nerves.
Thus, the localization, subtype and activity of ATP degrading enzymes, the presence of downstream extracellular ATP metabolites and expression of specific receptors should all shape the functional outcome of purinergic pain signalling in migraine. This area of research is in progress and needs further studies.
Basic properties of P2X3 receptors and their function in migraine mechanisms
The P2X3 receptor is the major ATP sensitive receptor subtype expressed in rodent trigeminal neurons (up to 80% of the whole population of trigeminal ganglion neurons in primary culture) . Concerning trigeminal ganglion neurons innervating the rat dura mater, retrograde labelling revealed P2X3 or P2X2 subtype (or both) expressed in 52% neurons . Extracellular ATP can operate at relatively low concentrations for activation of P2X3 receptors to which it has high affinity (EC50 ~ 1 μM) . When extracellular ATP is not efficiently hydrolyzed, it can inhibit P2X3 receptor at low nanomolar concentrations through a mechanism known as the ‘high affinity desensitization’ (HAD) [50, 51]. HAD is a P2X3 specific phenomenon as it is not observed with the P2X2 receptor subtype . Heteromerization of P2X3 subunits with slowly desensitizing P2X2 receptors is a common phenomenon in different types of sensory neurons [52, 53] and provides an additional transducer of nociceptive signals with lower adaptation.
The nerve fibers innervating meninges are nociceptive C- and Aδ-fibers [54,55,56] with their own repertoire of calcium, potassium and sodium channels plus nociceptive sensor proteins like P2X3 receptors [9, 26]. P2X3 receptors activated by ATP are highly expressed in nociceptive Aδ-fibers but also present in unmyelinated C-fibers [57, 58]. Indeed, in vivo topical application of ATP to rat meninges induces activation of approximately half population of C- and Aδ-fibers . In the isolated rat hemiskull preparation, both ATP and the stable ATP analogue α,β-meATP (agonist of P2X1 and P2X3 receptor subtypes) induce sustained spiking activity in meningeal afferents [26, 59]. An even stronger effect of ATP is observed in mouse meningeal afferents . Studies with the P2X2/3 antagonist A-317491 suggest that ATP may excite meningeal afferents via P2X3 and/or P2X2/3 receptors .
These data on the role of P2X2 and P2X3 receptors were obtained in in vitro conditions, when a prolonged application of exogenous ATP (or its analogues) only partially mimics the action of endogenous ATP which naturally takes place in restricted areas and is limited by the high activity of NTPDases. To overcome this experimental limitation, our modelling study  has simulated the action of endogenous ATP released from meningeal mast cells and has indicated that a sustained pro-nociceptive effect of ATP could be achieved via: i) multiple ATP release sites; ii) highly branched axon fibers; iii) coupling of desensitizing P2X3 receptors with slowly desensitizing P2X2 receptors; and iv) co-expression of Nav1.8 sodium channels that have fast recovery from voltage-dependent inactivation. While P2X2 receptors are less expressed in sensory neurons , especially in human ones , human P2X3 receptors recover from desensitization much faster than rodent ones , thus supporting a more persistent process for pain signalling.
In accordance with the International Classification of Headache Disorders (third edition), tension headache is another primary headache associated with tenderness of pericranial muscles . Interestingly, injection of ATP into the trapezius muscle of a small group of healthy volunteers produces more pain compared to placebo . Moreover, local injection of ATP (or a,b-meATP) into neck muscles induces strong, prolonged facilitation of nociceptive signaling in brainstem networks [64,65,66]. This effect of ATP is intensified after inhibition of ADP sensitive P2Y1 receptors  consistent with inhibitory control of P2X3 receptors by the ADP sensitive P2Y1 subtype  (Fig. 1). One possible mechanism of headache originating from neck muscles may be related to the branching of trigeminal neurons that can functionally connect intra- and extracranial areas [67, 68].
Branching of meningeal afferents could also contribute to enhanced antidromic sensory spiking by supplying signalling from axon collaterals or the trigeminal ganglion itself [69,70,71]. Antidromic spiking is supposed to initiate local CGRP release, vasodilation, and degranulation of mast cells, all events which are leading to sterile meningeal neuroinflammation . Our recent study has provided direct evidence that spiking activity can actually be propagated from central trigeminal fibers to the peripheral terminals in the meninges . Importantly, this study has shown that ATP receptors are present not only at the peripheral nerve terminals but also in more central parts of the nerve fibers extending our view on the principal mechanisms of peripheral nociception. We cannot exclude that P2X3 or P2X2/3 receptors are also widely expressed along the nonmyelinated C- fibers or located in the nodes of Ranvier of Aδ-fibers analogous to recently proposed location of CGRP receptors . Taken together, these data cast some light on the involvement of P2X3 and P2X2/3 complexes in purinergic mechanisms contributing to trigeminal pain.
In the trigeminovascular system, in addition to nerve fibres, the local vessels and the process of nucleotide homeostasis (and signalling) may also be essential contributors to migraine pathology. These meningeal vessels, like other tissues constituting the trigeminovascular system, can be both a source and the target for the modulatory action of ATP. On such vessels, ATP can regulate the vascular tone directly via metabotropic P2Y13 and ionotropic P2X1 receptors promoting vasoconstriction [47, 73]. Conversely, the vessel vasodilatory effect of ATP may be observed after activation of P2X3 receptors on trigeminal neurons in the ganglion to trigger antidromic CGRP release in the meninges [47, 73]. Which one of the two contrasting actions is more relevant for migraine pain remains to be established.
In approximately 30% migraineurs the headache attack is preceded by an aura , i.e. a set of symptoms comprising visual dysfunction generated by a large wave of depolarization of the cerebral cortex termed cortical spreading depression (CSD) [5, 75]. A former study  has demonstrated that CSD is a sufficient trigger for ATP release in the cerebral cortex. The question then arises as to whether CSD might be a strong stimulus to release ATP at meningeal level as well. A direct answer to this question is currently missing. Nonetheless, it has been shown  that, in the fully anaesthetized rat, experimentally evoked CSD can activate about half of trigeminal nociceptors, a value similar to the responses to focally applied ATP. Even though this coincidence does not imply a causal link between two observations, these results suggest that ATP can induce excitation of trigeminal nociceptors in vivo even under deep anaesthesia. The implication of these data is that ATP-mediated activity might be important to understand different mechanisms of migraine with as well as without aura.
Neuro-immune synapses and role of immune cells in meningeal nociception
Meningeal tissues contain various immune cells [77, 78]. Of special interest are local mast cells which synthesize a plethora of active molecules including ATP, hormones, cytokines, neurotrophins, all to be released in a stimulus-specific manner [79, 80]. These cells are located in close proximity to nerve fibers, forming a sort of meningeal neuro-immune synapse [81, 82] (Fig. 2). Notably, these mast cells could serve both as the target for ATP acting via P2X7 receptors [27, 83, 84] and as an additional source of ATP release .
The action of ATP on mast cells induces release of endogenous serotonin which can further amplify nociceptive signalling. Thus, ATP can combine two modes of nociceptive action on the meninges, namely, one through degranulating mast cells and release of serotonin to excite nerve terminals via 5-HT3 receptors, and the other one through a direct action on fibers via P2X3 receptors  (Fig. 2).
Immune cells in the meninges are associated with the local meningeal lymphatic system [87, 88] that provides a mechanism to clear metabolic waste from the brain and meninges themselves . Consistent with the view that ATP, acting via P2X7 receptors, can trigger pro-inflammatory processes activating dural immune cells [27, 83, 84], we have observed that the P2X7-preferring agonist BzATP enhances release of the pro-inflammatory tumor necrosis factor-α (TNFα) and of the anti-inflammatory cytokine Il-10, both implicated in migraine pain [90, 91]. Nevertheless, the release of these cytokines is similar in WT and KO mice lacking the meningeal lymphatic system . Furthermore, activation by ATP of meningeal afferents is not more effective in mice lacking meningeal lymphatics .
P2X3 receptors and neuronal sensitization in migraine
While the neuropeptide CGRP is considered a major contributor to the onset of migraine attacks  and has multifarious effects on neurons and immune cells in the CNS , we propose that one important target for the CGRP algogenic action is the P2X3 receptor. Progress in understanding the molecular mechanisms of such an action of CGRP has come from the use of an in vitro model of mouse trigeminal ganglia where it has been shown that CGRP (at submicromolar concentrations) selectively binds to sensory neurons expressing P2X3 receptors without generating any direct change in their membrane current [16, 93]. Nonetheless, in the presence of CGRP, P2X3 receptor mediated responses become gradually larger with a significant upward shift of their agonist concentration response curve, indicating enhanced efficacy of P2X3 receptor activation . It is important to note that this effect of CGRP has a delayed onset that develops over at least one hour and, therefore, mimics the slow, insidious onset of migraine headache when the peak concentration of serum CGRP in humans occurs about one hour after the start of pain . The P2X3 receptor sensitization is obtained through a variety of mechanisms that comprise accelerated recovery from their desensitization, and augmented P2X3 receptor expression at membrane level due to facilitated trafficking of such molecules via intracellular activation of PKA and PKC dependent processes . It is interesting that the P2X3 potentiation persists for hours after washout of CGRP, and further involves an increased synthesis of P2X3 receptors plus facilitated release of BDNF that exerts its own algogenic effect . These observations outline a basic cellular process for extended sensitization of trigeminal sensory neurons to subsequent noxious stimuli.
One further synergic purinergic mechanism presumably closely involved in the algogenic effect of CGRP is mediated by the metabotropic P2Y receptors of glial cells. In fact, the strong algogenic peptide bradykinin stimulates release of CGRP by neurons to engage P2Y receptors of satellite glial cells with subsequent increase in intracellular Ca2+ and liberation of inflammatory cytokines that can sustain and amplify pain mechanisms . Interestingly, activation of P2X3 receptors in the trigeminal ganglion can also release CGRP and dilate the middle meningeal artery , thus prolonging local neuroinflammation and neuronal sensitization.
These observations based on in vitro experiments provide a set of molecular mechanisms to support the pivotal role of CGRP in migraine, suggest a close coupling among neuronal and glial processes, and are consistent with the present treatment of migraine with pharmacological blockers of CGRP [13, 97].
The scenario of pain inducing agents impacting on P2X receptors is broad and should include the neurotrophin NGF that, independent from CGRP activity, produces multiple effects on such receptors of trigeminal sensory neurons. Thus, NGF accelerates recovery from desensitization of P2X3 receptors and induces splice variants of the P2X2 subtype favouring the expression of heteromeric receptors . Nevertheless, it is difficult to employ anti-NGF treatment for pain suppression as NGF produces many beneficial effects, in particular, via TrkA receptor activity. However, the latter limitation could be overcome by uncoupling TrkA from PLCγ signalling without inhibiting the TrkA catalytic activity . This approach should avoid the unwanted effects of direct TrkA inhibition and probably can be used for anti-nociceptive applications in migraine and other pain conditions. It is noteworthy that NGF can be used without eliciting significant pain when it is administered as human NGF mutant (hNGF P61F) that has minimal nociceptive action, thus making it an interesting candidate for clinical use in NGF-deficit conditions without affecting the nociceptive system .
While endogenous substances like CGRP, BDNF or NGF might operate sequentially or in parallel to trigger trigeminal pain, an important downstream process accompanying their action is the generation of an inflammatory milieu contributing to the establishment and extension of nociceptive dysfunction. This concept accords with the original hypothesis that chronic migraine is caused by an ongoing “sterile inflammation” that renders patients susceptible to frequent relapse [101,102,103]. In support of this theory, adding inflammatory cells like macrophages to cultured trigeminal neurons enhances P2X3 receptor activity likely because of the inflammatory agents released by such cells . Thus, application of a standard inflammatory agent like lipopolysaccharide to trigeminal neurons slowly evokes a rise in functional responses of P2X3 receptors  probably in view of the action of TNFα, released during inflammation to strongly sensitize trigeminal sensory neurons [105,106,107,108].
It should be noted that these data, indicating new mechanisms of purinergic modulation, were obtained on neurons isolated mainly from young animals and, therefore, need further validation in in vivo models of migraine, including adult animals.
P2X3 receptors in familial type migraine
A relatively rare type of migraine is familial hemiplegic migraine (FHM), a severe, monogenic disease that comprises three subtypes among which type 1 (FHM1) is the most frequently observed . A widely studied mutation found in FHM1 is the R192Q of the Cacna1a gene coding for the α1 subunit of Cav2.1 channels  that confers a gain of function to these voltage gated channels predominantly expressed by neurons .
Generation of knockin (KI) mice postnatally expressing this mutation has provided a powerful model of migraine  as these animals present symptoms consistent with human migraine . Furthermore, cultured trigeminal neurons from FHM1 mice show strong functional upregulation of their P2X3 receptors  likely due to enhanced basal levels of CGRP and BDNF  that is translated into increased excitability with stronger action potential firing of trigeminal ganglion neurons .
Nonetheless, testing CGRP release in FHM1 mouse tissues has revealed a complexity of this mechanisms likely related to the age of animals and methodological considerations that include the sampled area, the low yield of endogenous peptide and the origin of CGRP. Indeed, Fioretti et al. (2011) have reported no difference in basal CGRP release from WT or KI trigeminal ganglia although K+-evoked release was found to be larger from KI ganglia . Conversely, Chan et al. (2019) have studied the central trigeminal nuclei in adult animals where they found no change in evoked CGRP release from KI tissue . Perhaps the role of endogenous CGRP in this mouse model might be better clarified in the future by applying selective chemical antagonists of CGRP receptors to find out how neuronal responses are changed to indicate any constitutively higher or stimulus-dependent concentration of this neuropeptide.
The molecular mechanisms responsible for higher activity of P2X3 receptors in this transgenic model also include tighter association between P2X3 receptors and the calcium/calmodulin-dependent serine protein kinase (CASK)  that leads to preferential compartmentalization of P2X3 receptors to membrane lipid rafts and more efficient P2X3 receptor function .
The phenotype produced by the R192Q mutation is, however, complex because it includes not only factors upregulating P2X3 receptors but also mechanisms that dysregulate their constitutive inhibition. One of them is represented by the brain natriuretic peptide (BNP), a blood borne peptide whose membrane receptors are strongly co-expressed with P2X3 receptors of trigeminal sensory neurons . Via cGMP-dependent intracellular pathways, BNP constitutively limits the activity of P2X3 receptors, a process that is largely depressed in the FHM1 phenotype . In addition, FHM1 mice show upregulation of the Nav1.7 subtype of voltage gated sodium channel  that contributes to their enhanced excitability.
Thus, the FHM1 mouse model has allowed identification of a series of dysregulated molecular mechanisms that synergize to facilitate firing of trigeminal sensory neurons, and it has provided a useful tool to test novel therapeutic approaches. The FHM1 model is, therefore, an experimental channelopathy that can be most useful to understand the role of Cav2.1 channels not only in migraine  but also in a variety of other neurological syndromes like some forms of epilepsy, ataxia and dystonia .
Endogenous P2X3 antagonists and pharmacological perspectives in migraine
Transmembrane P2X3 receptors with their extensive extracellular domain  contains several sites for binding allosteric modulators. Of special interest to the aims of the current review are modulators which might be used to control migraine pain generation. Notably, given the specific properties of ionotropic P2X3 receptors (very fast desensitization with slow recovery), these agents, apart from classical competitive and non-competitive antagonism, might selectively modulate desensitization. For instance, inhibition of P2X3 receptors mediated signalling could either include promotion of desensitization onset or slowing down the recovery process (reviewed in ). Several studies suggested pharmacological and native substances to target desensitization in order to obtain an antinociceptive action [126, 127].
Magnesium and calcium ions are the potent modulators of P2X3 receptor function providing opposite effects on receptor recovery from desensitization [128, 129]. The magnesium effect is of special interest to migraine pathology as some studies have suggested that migraine is associated with magnesium deficiency . However, there are contrasting views on the use of magnesium as an aid to preventive migraine therapy [131, 132]. Magnesium is the natural blocker of NMDA receptors, which are one of the main glutamate receptor subtypes in the CNS and the main determinants of CSD related to migraine aura [133, 134]. Our previous studies indicated that magnesium deprivation promotes glutamate induced firing of nerve terminals via NMDA receptors  suggesting its role in the control of excitability of meningeal afferents. Magnesium can, however, directly inhibit P2X3 receptors , making it difficult to select the preferred target of anti-nociception against a potential sensitization of trigeminal firing. In contrast, extracellular calcium can strongly accelerate recovery from desensitization of P2X3 receptors , apparently competing with magnesium . An analysis of genetic co-heritability and causality using data from the International Headache Consortium (23,285 cases, 95,425 controls) and circulating serum calcium levels (39,400 subjects) has revealed co-occurrence of migraine and hypercalcaemia, and it has suggested a causal link and increased risk of migraine with high serum calcium . Of interest is the ability of bone cancer treatment drugs bisphosphonates to promote synthesis of the ATP endogenous analogue ApppI, which potently and specifically inhibits P2X3 receptors of trigeminal neurons .
P2X3 receptors are highly sensitive to changes in ambient temperature. Early studies with mice lacking P2X3 receptors have indicated that these transgenic animals are unable to code warm stimuli . Subsequent studies have identified molecular mechanisms underlying the unusual sensitivity of P2X3 to temperature. Thus, while the onset of desensitization appears to be apparently temperature insensitive, recovery from desensitization accelerates with heat (Q10 ~ 10) . Another interesting observation is that HAD by ambient nanomolar ATP which limits the function of P2X3 receptors , is much less effective at normal body temperatures . Using total internal reflection fluorescence microscopy coupled with functional recovery after photobleaching, we have found that the peri-membrane turnover of P2X3 receptors had Q10 ∼4.5 suggesting that P2X3 receptor trafficking to plasma membrane is also highly temperature-sensitive . These data also suggest the potential role of P2X3 receptors in the well-known analgesic effects of cooling.
It is well stabilised that females are more prone to migraine than men [139, 140]. Menstrual migraine is a primary headache especially difficult to treat and often persistent . Because the level of female hormones (progesterone and oestrogens) falls in the perimenstrual period , oestrogen replacement therapy has been suggested to inhibit migraine pain . Accumulating data indicate that oestrogen regulates P2X receptors through genomic and non-genomic pathways [143, 144], potentially contributing to the sex difference in pain and probably in migraine susceptibility. However, to date, there is no systematic analysis of sexual dimorphism of P2X3 receptors in the trigeminal nociceptive system.
Since the discovery of the selective expression of P2X3 receptors in sensory neurons, many research groups have focused on the development of specific antagonists aiming to inhibit painful signalling [58, 145,146,147,148,149,150]. Potentially, these selective P2X3 and P2X2/3 inhibitors may have implication for the treatment of migraine pain. Nevertheless, to the best of our knowledge, no clinical trials have been reported testing P2X3 antagonists in migraine. At the present time, these studies mainly deal with treating chronic cough and hypertension. For instance, potent P2X3 and P2X2/3 inhibitors are already at an advanced stage of clinical trial for the treatment of chronic cough [151, 152]. The main side effect of P2X2/3 antagonists is the loss of taste sensation  although the selective P2X3 antagonist BLU-5937 is apparently lacking such an effect . It is, however, clear that there is a dearth of studies with selective P2X3 receptor antagonists in migraine pain either experimentally or clinically. A void that the present review might help to fill.
P2X3 receptors selectively expressed in sensory neurons and enriched in the trigeminal nociceptive system have unique functional characteristics including synergy with pronociceptive CGRP signalling. Thus, the P2X3 receptor represents an attractive molecular target for innovative approaches to inhibit trigeminal pain in migraine. Future studies in vivo should investigate the therapeutic potential of blocking selectively P2X3 or P2X2/3 receptors in migraine pathology to validate their potential translational value.
Availability of data and materials
Calcitonin gene related peptide
Ecto-nucleoside triphosphate diphosphohydrolase
Cyclic adenosine monophosphate
High affinity desensitization
Tumor necrosis factor alpha
Cortical spreading depression
Protein kinase A
Protein kinase C
Brain-derived neurothrophic factor
Nerve growth factor
Tropomyosin receptor kinase A
Phospholipase C gamma
Familial hemiplegic migraine
Calcium/calmodulin-dependent serine protein kinase
Brain natriuretic peptide
Cyclic guanosine monophosphate
1-Adenosine-5′-yl ester 3-(3-methylbut-3-enyl) triphosphoric acid diester
Edvinsson L (2022) Calcitonin gene-related peptide (CGRP) is a key molecule released in acute migraine attacks-Successful translation of basic science to clinical practice. J Intern Med 292(4):575–586. https://doi.org/10.1111/JOIM.13506
Ferrari MD, Goadsby PJ, Burstein R et al (2022) Migraine. Nat Rev Dis Primers 8(1):2. https://doi.org/10.1038/S41572-021-00328-4
Sudershan A, Mahajan K, Singh K et al (2022) The complexities of migraine: A debate among migraine researchers: a review. Clin Neurol Neurosurg 214:107136. https://doi.org/10.1016/J.CLINEURO.2022.107136
Messlinger K (2009) Migraine: where and how does the pain originate? Exp Brain Res 196:179–193. https://doi.org/10.1007/s00221-009-1756-y
Pietrobon D, Moskowitz MA (2013) Pathophysiology of Migraine. Annu Rev Physiol 75:365–391. https://doi.org/10.1146/annurev-physiol-030212-183717
Olesen J, Burstein R, Ashina M, Tfelt-Hansen P (2009) Origin of pain in migraine: evidence for peripheral sensitisation. Lancet Neurol 8:679–690. https://doi.org/10.1016/S1474-4422(09)70090-0
Strassman AM, Raymond SA, Burstein R (1996) Sensitization of meningeal sensory neurons and the origin of headaches. Nature 384:560–564. https://doi.org/10.1038/384560a0
Rattanawong W, Rapoport A, Srikiatkhachorn A (2022) Neurobiology of migraine progression. Neurobiol. Pain 12:100094. https://doi.org/10.1016/J.YNPAI.2022.100094
Giniatullin R (2020) Ion channels of nociception. Int J Mol Sci 21(10):3553. https://doi.org/10.3390/ijms21103553
Iannone LF, de Logu F, Geppetti P, de Cesaris F (2022) The role of TRP ion channels in migraine and headache. Neurosci Lett 768:136380. https://doi.org/10.1016/J.NEULET.2021.136380
Ashina M, Hansen JM, Do TP et al (2019) Migraine and the trigeminovascular system—40 years and counting. Lancet Neurol 18:795–804. https://doi.org/10.1016/S1474-4422(19)30185-1
Edvinsson L (2022) Calcitonin gene‐related peptide (CGRP) is a key molecule released in acute migraine attacks—Successful translation of basic science to clinical practice. J Intern Med. https://doi.org/10.1111/joim.13506
Sacco S, Amin FM, Ashina M et al (2022) European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene related peptide pathway for migraine prevention – 2022 update. J Headache Pain 23:67. https://doi.org/10.1186/s10194-022-01431-x
Iyengar S, Johnson KW, Ossipov MH, Aurora SK (2019) CGRP and the Trigeminal System in Migraine. Headache 59:659–681. https://doi.org/10.1111/head.13529s
Melo-Carrillo A, Strassman AM, Nir RR et al (2017) Fremanezumab—a humanized monoclonal anti-cgrp antibody—inhibits thinly myelinated (Aδ) but not unmyelinated (c) meningeal nociceptors. J Neurosci 37:10587–10596. https://doi.org/10.1523/JNEUROSCI.2211-17.2017
Fabbretti E, D’Arco M, Fabbro A et al (2006) Delayed upregulation of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide. J Neurosci 26(23):6163–71. https://doi.org/10.1523/JNEUROSCI.0647-06.2006
Collier HOJ, James GWL, Schneider C (1966) Antagonism by aspirin and fenamates of bronchoconstriction and nociception induced by adenosine-5′-triphosphate . Nature 212:411–412
Coutts AA, Jorizzo JL, Eady RAJ et al (1981) Adenosine triphosphate-evoked vascular changes in human skin: Mechanism of action. Eur J Pharmacol 76:391–401. https://doi.org/10.1016/0014-2999(81)90110-2
Burnstock G (1996) A unifying purinergic hypothesis for the initiation of pain. Lancet 347:1604–1605. https://doi.org/10.1016/S0140-6736(96)91082-X
Burnstock G, Kennedy C (1985) Is there a basis for distinguishing two types of P2-purinoceptor? Gen Pharmacol 16:433–440
Souslova V, Cesare P, Ding Y et al (2000) Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature 407:1015–1017. https://doi.org/10.1038/35039526
Cockayne DA, Hamilton SG, Zhu QM et al (2000) Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 407:1011–1015. https://doi.org/10.1038/35039519
Wirkner K, Sperlagh B, Illes P (2007) P2X3 receptor involvement in pain states. Mol Neurobiol 36:165–183. https://doi.org/10.1007/s12035-007-0033-y
Burnstock G (1981) Pathophysiology of migraine: a new hypothesis. Lancet 317:1397–1399. https://doi.org/10.1016/S0140-6736(81)92572-1
Ralevic V, Burnstock G (1998) Receptors for purines and pyrimidines. Pharmacol Rev 50:413–492. https://doi.org/10.1007/978-3-642-28863-0_5
Yegutkin GG, Guerrero-Toro C, Kilinc E et al (2016) Nucleotide homeostasis and purinergic nociceptive signaling in rat meninges in migraine-like conditions. Purinergic Signal 12(3):561–74. https://doi.org/10.1007/s11302-016-9521-8
Koroleva K, Gafurov O, Guselnikova V et al (2019) Meningeal mast cells contribute to ATP-induced nociceptive firing in trigeminal nerve terminals: Direct and indirect purinergic mechanisms triggering migraine pain. Front Cell Neurosci 13:195. https://doi.org/10.3389/fncel.2019.00195
Zhao J, Levy D (2015) Modulation of intracranial meningeal nociceptor activity by cortical spreading depression: A reassessment. J Neurophysiol 113:2778–2785. https://doi.org/10.1152/JN.00991.2014
Lalo U, Palygin O, Rasooli-Nejad S et al (2014) Exocytosis of ATP from astrocytes modulates phasic and tonic inhibition in the neocortex. PLoS Biol 12(1):e1001747. https://doi.org/10.1371/JOURNAL.PBIO.1001747
Pangršič T, Potokar M, Stenovec M et al (2007) Exocytotic release of ATP from cultured astrocytes. J Biol Chem 282(39):28749–28758. https://doi.org/10.1074/jbc.M700290200
Burnstock G (2004) Cotransmission. Curr Opin Pharmacol 4:47–52. https://doi.org/10.1016/J.COPH.2003.08.001
Simonetti M, Fabbro A, D’Arco M, et al (2006) Comparison of P2X and TRPVI receptors in ganglia or primary culture of trigeminal neurons and their modulation by NGF or serotonin. Mol Pain 2. https://doi.org/10.1186/1744-8069-2-11
Yegutkin GG (2008) Nucleotide- and nucleoside-converting ectoenzymes: Important modulators of purinergic signalling cascade. Biochim Biophys Acta 1783:673–694. https://doi.org/10.1016/J.BBAMCR.2008.01.024
Pelegrin P, Surprenant A (2006) Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J 25:5071–5082. https://doi.org/10.1038/SJ.EMBOJ.7601378
Chiu YH, Ravichandran KS, Bayliss DA (2014) Intrinsic properties and regulation of Pannexin 1 channel. Channels (Austin) 8:103–109. https://doi.org/10.4161/CHAN.27545
Joseph EK, Green PG, Levine JD (2014) ATP Release Mechanisms of Endothelial Cell-Mediated Stimulus-Dependent Hyperalgesia. J Pain 15:771–777. https://doi.org/10.1016/J.JPAIN.2014.04.005
Coste B, Mathur J, Schmidt M et al (1979) (2010) Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330:55–60. https://doi.org/10.1126/science.1193270
Wang SP, Chennupati R, Kaur H et al (2016) Endothelial cation channel PIEZO1 controls blood pressure by mediating flow-induced ATP release. J Clin Invest 126:4527–4536. https://doi.org/10.1172/JCI87343
Mikhailov N, Leskinen J, Fagerlund I et al (2019) Mechanosensitive meningeal nociception via Piezo channels: Implications for pulsatile pain in migraine? Neuropharmacology 149:113–123. https://doi.org/10.1016/j.neuropharm.2019.02.015
Dolgorukova A, Isaeva JE, Verbitskaya E et al (2021) Differential effects of the Piezo1 agonist Yoda1 in the trigeminovascular system: an electrophysiological and intravital microscopy study in rats. Exp Neurol 339:113634. https://doi.org/10.1016/j.expneurol.2021.113634
Pietra AD, Mikhailov N, Giniatullin R (2020) The emerging role of mechanosensitive piezo channels in migraine pain. Int J Mol Sci 21(3):696. https://doi.org/10.3390/ijms21030696
Sokolov AY, Volynsky MA, Zaytsev V v., et al (2021) Advantages of imaging photoplethysmography for migraine modeling: new optical markers of trigemino‐vascular activation in rats. J Headache Pain 22.https://doi.org/10.1186/s10194-021-01226-6
Villa G, Fumagalli M, Verderio C et al (2010) Expression and contribution of satellite glial cells purinoceptors to pain transmission in sensory ganglia: an update. Neuron Glia Biol 6:31–42. https://doi.org/10.1017/S1740925X10000086
Gerevich Z, Zadori Z, Müller C et al (2007) Metabotropic P2Y receptors inhibit P2X3 receptor-channels via G protein-dependent facilitation of their desensitization. Br J Pharmacol 151:226–236. https://doi.org/10.1038/SJ.BJP.0707217
Haanes KA, Labastida-Ramírez A, Chan KY et al (2018) Characterization of the trigeminovascular actions of several adenosine A2A receptor antagonists in an in vivo rat model of migraine. J Headache Pain 19(1):41. https://doi.org/10.1186/s10194-018-0867-x
Thuraiaiyah J, Kokoti L, Al-Karagholi MAM, Ashina M (2022) Involvement of adenosine signaling pathway in migraine pathophysiology: a systematic review of preclinical studies. J Headache Pain 23(1):43. https://doi.org/10.1186/s10194-022-01412-0
Haanes KA, Edvinsson L (2014) Expression and characterization of purinergic receptors in rat middle meningeal artery-potential role in migraine. PLoS One 9(9):e108782. https://doi.org/10.1371/JOURNAL.PONE.0108782
Staikopoulos V, Sessle BJ, Furness JB, Jennings EA (2007) Localization of P2X2 and P2X3 receptors in rat trigeminal ganglion neurons. Neuroscience 144:208–216. https://doi.org/10.1016/J.NEUROSCIENCE.2006.09.035
North RA (2004) P2X3 receptors and peripheral pain mechanisms. J Physiol 554(2):301–8
Pratt EB, Brink TS, Bergson P et al (2005) Use-dependent inhibition of P2X3 receptors by nanomolar agonist. J Neurosci 25:7359–7365. https://doi.org/10.1523/JNEUROSCI.5189-04.2005
Sokolova E, Skorinkin A, Moiseev I, et al (2006) Experimental and modeling studies of desensitization of P2X<inf>3</inf> receptors. MolPharmacol 70. https://doi.org/10.1124/mol.106.023564
Illes P, Müller CE, Jacobson KA, et al (2021) Update of P2X receptor properties and their pharmacology: IUPHAR Review 30. Br J Pharmacol 178. https://doi.org/10.1111/BPH.15299
North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82:1013–1067. https://doi.org/10.1152/PHYSREV.00015.2002
Fricke B, Andres KH, von Düring M (2001) Nerve fibers innervating the cranial and spinal meninges: Morphology of nerve fiber terminals and their structural integration. Microsc Res Tech 53:96–105. https://doi.org/10.1002/jemt.1074
Eftekhari S, Warfvinge K, Blixt FW, Edvinsson L (2013) Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J Pain 14:1289–1303. https://doi.org/10.1016/j.jpain.2013.03.010
Meßlinger K, Hanesch U, Baumgärtel M et al (1993) Innervation of the dura mater encephali of cat and rat: ultrastructure and calcitonin gene-related peptide-like and substance P-like immunoreactivity. Anat Embryol (Berl) 188:219–237. https://doi.org/10.1007/BF00188214
Sato M, Sato T, Yajima T et al (2018) The transient receptor potential cation channel subfamily V members 1 and 2, P2X purinoceptor 3 and calcitonin gene-related peptide in sensory neurons of the rat trigeminal ganglion, innervating the periosteum, masseter muscle and facial skin. Arch Oral Biol 96:66–73. https://doi.org/10.1016/j.archoralbio.2018.08.012
Ford AP (2012) In pursuit of P2X3 antagonists: Novel therapeutics for chronic pain and afferent sensitization. Purinergic Signal 8(Suppl 1):3–26. https://doi.org/10.1007/s11302-011-9271-6
Zakharov A, Koroleva K, Giniatullin R (2016) Clustering Analysis for Sorting ATP-Induced Nociceptive Firing in rat Meninges. Bionanoscience 6. https://doi.org/10.1007/s12668-016-0276-z
Suleimanova A, Talanov M, Gafurov O et al (2020) Modeling a Nociceptive Neuro-Immune Synapse Activated by ATP and 5-HT in Meninges: Novel Clues on Transduction of Chemical Signals Into Persistent or Rhythmic Neuronal Firing. Front Cell Neurosci 14:135. https://doi.org/10.3389/fncel.2020.00135
Serrano A, Mo G, Grant R et al (2012) Differential expression and pharmacology of native P2X receptors in rat and primate sensory neurons. J Neurosci 32:11890–11896. https://doi.org/10.1523/JNEUROSCI.0698-12.2012
Olesen J (2018) Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 38:1–211
Mørk H, Ashina M, Bendtsen L et al (2003) Experimental muscle pain and tenderness following infusion of endogenous substances in humans. Eur J Pain 7:145–153. https://doi.org/10.1016/S1090-3801(02)00096-4
Reitz M, Makowska A, Ellrich J (2009) Excitatory and inhibitory purinergic control of neck muscle nociception in anaesthetized mice. Cephalalgia 29:58–67. https://doi.org/10.1111/J.1468-2982.2008.01700.X
Ristic D, Spangenberg P, Ellrich J (2011) Acetylsalicylic acid inhibits α, β-meATP-induced facilitation of neck muscle nociception in mice - Implications for acute treatment of tension-type headache. Eur J Pharmacol 673:13–19. https://doi.org/10.1016/j.ejphar.2011.10.008
Ellrich J, Makowska A (2007) Nerve growth factor and ATP excite different neck muscle nociceptors in anaesthetized mice. Cephalalgia 27:1226–1235. https://doi.org/10.1111/j.1468-2982.2007.01431.x
Ellrich J, Andersen OK, Messlinger K, Arendt-Nielsen L (1999) Convergence of meningeal and facial afferents onto trigeminal brainstem neurons: an electrophysiological study in rat and man. Pain 82:229–237. https://doi.org/10.1016/S0304-3959(99)00063-9
Schueler M, Messlinger K, Dux M et al (2013) Extracranial projections of meningeal afferents and their impact on meningeal nociception and headache. Pain 154:1622–1631. https://doi.org/10.1016/j.pain.2013.04.040
Geppetti P, Rossi E, Chiarugi A, Benemei S (2012) Antidromic vasodilatation and the migraine mechanism. J Headache Pain 13:103–111. https://doi.org/10.1007/S10194-011-0408-3
Gafurov O, Koroleva K, Giniatullin R (2021) Antidromic Spike Propagation and Dissimilar Expression of P2X, 5-HT, and TRPV1 Channels in Peripheral vs. Central Sensory Axons in Meninges. Front Cell Neurosci 14. https://doi.org/10.3389/fncel.2020.623134
Sorkin LS, Eddinger KA, Woller SA, Yaksh TL (2018) Origins of antidromic activity in sensory afferent fibers and neurogenic inflammation. Semin Immunopathol 40:237–247. https://doi.org/10.1007/S00281-017-0669-2
Edvinsson JCA, Warfvinge K, Krause DN et al (2019) C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system. J Headache Pain 20(1):105. https://doi.org/10.1186/S10194-019-1055-3
Haanes KA, Labastida-Ramírez A, Blixt FW et al (2019) Exploration of purinergic receptors as potential anti-migraine targets using established pre-clinical migraine models. Cephalalgia 39:1421–1434. https://doi.org/10.1177/0333102419851810
Russell MB, Olesen J (1995) Increased familial risk and evidence of genetic factor in migraine. BMJ 311:541. https://doi.org/10.1136/BMJ.311.7004.541
Ayata C, Lauritzen M (2015) Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature. Physiol Rev 95:953–993. https://doi.org/10.1152/PHYSREV.00027.2014
Karatas H, Erdener SE, Gursoy-Ozdemir Y et al (2013) Spreading depression triggers headache by activating neuronal Panx1 channels. Science 339(6123):1092–5. https://doi.org/10.1126/SCIENCE.1231897
McIlvried LA, Borghesi LA, Gold MS (2015) Sex-, Stress-, and Sympathetic Post-Ganglionic Neuron-Dependent Changes in the Expression of Pro- and Anti-Inflammatory Mediators in Rat Dural Immune Cells. Headache 55:943–957. https://doi.org/10.1111/HEAD.12596
Balcziak LK, Russo AF (2022) Dural Immune Cells, CGRP, and Migraine. Front Neurol 13:874193. https://doi.org/10.3389/fneur.2022.874193
Theoharides TC, Kempuraj D, Tagen M et al (2007) Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev 217:65–78. https://doi.org/10.1111/j.1600-065X.2007.00519.x
Theoharides TC (2020) The impact of psychological stress on mast cells. Ann Allergy Asthma Immunol 125:388–392. https://doi.org/10.1016/J.ANAI.2020.07.007
Koyuncu Irmak D, Kilinc E, Tore F (2019) Shared Fate of Meningeal Mast Cells and Sensory Neurons in Migraine. Front Cell Neurosci 13:136. https://doi.org/10.3389/fncel.2019.00136
Giniatullin R (2022) 5-hydroxytryptamine in migraine: The puzzling role of ionotropic 5-HT<inf>3</inf> receptor in the context of established therapeutic effect of metabotropic 5-HT<inf>1</inf> subtypes. Br J Pharmacol 179(3):400–415. https://doi.org/10.1111/bph.15710
Nurkhametova D, Siniavin A, Streltsova M et al (2020) Does Cholinergic Stimulation Affect the P2X7 Receptor-Mediated Dye Uptake in Mast Cells and Macrophages? Front Cell Neurosci 14:548376. https://doi.org/10.3389/fncel.2020.548376
Nurkhametova D, Kudryavtsev I, Guselnikova V et al (2019) Activation of P2X7 receptors in peritoneal and meningeal mast cells detected by uptake of organic dyes: Possible purinergic triggers of neuroinflammation in meninges. Front Cell Neurosci 13:45. https://doi.org/10.3389/fncel.2019.00045
Wang L, Sikora J, Hu L et al (2013) ATP release from mast cells by physical stimulation: a putative early step in activation of acupuncture points. Evid Based Complement Alternat Med 2013:350949. https://doi.org/10.1155/2013/350949
Koroleva K, Ermakova E, Mustafina A et al (2020) Protective Effects of Hydrogen Sulfide Against the ATP-Induced Meningeal Nociception. Front Cell Neurosci 14:266. https://doi.org/10.3389/fncel.2020.00266
Louveau A, Plog BA, Antila S et al (2017) Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest 127:3210–3219. https://doi.org/10.1172/jci90603
Aspelund A, Antila S, Proulx ST et al (2015) A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med 212:991–999. https://doi.org/10.1084/jem.20142290
Raper D, Louveau A, Kipnis J (2016) How do meningeal lymphatic vessels drain the CNS? Trends Neurosci 39:581–586. https://doi.org/10.1016/j.tins.2016.07.001
Munno I, Marinaro M, Bassi A et al (2001) Immunological aspects in migraine: increase of IL-10 plasma levels during attack. Headache 41:764–767. https://doi.org/10.1046/J.1526-4610.2001.01140.X
Perini F, D’Andrea G, Galloni E et al (2005) Plasma cytokine levels in migraineurs and controls. Headache 45:926–931. https://doi.org/10.1111/J.1526-4610.2005.05135.X
Mikhailov N, Virenque A, Koroleva K et al (2022) The role of the meningeal lymphatic system in local meningeal inflammation and trigeminal nociception. Sci Rep 12:8804. https://doi.org/10.1038/s41598-022-12540-7
Simonetti M, Giniatullin R, Fabbretti E (2008) Mechanisms mediating the enhanced gene transcription of P2X<inf>3</inf> receptor by calcitonin gene-related peptide in trigeminal sensory neurons. J Biol Chem 283(27):18743–52. https://doi.org/10.1074/jbc.M800296200
Sarchielli P, Alberti A, Codini M et al (2000) Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks. Cephalalgia 20:907–918. https://doi.org/10.1046/j.1468-2982.2000.00146.x
Ceruti S, Villa G, Fumagalli M et al (2011) Calcitonin gene-related peptide-mediated enhancement of purinergic neuron/glia communication by the algogenic factor bradykinin in mouse trigeminal ganglia from wild-type and R192Q Cav2.1 Knock-in mice: implications for basic mechanisms of migraine pain. J Neurosci 31:3638–3649. https://doi.org/10.1523/JNEUROSCI.6440-10.2011
Haanes KA, Labastida-Ramírez A, Blixt FW et al (2019) Exploration of purinergic receptors as potential anti-migraine targets using established pre-clinical migraine models. Cephalalgia 39(11):1421–1434. https://doi.org/10.1177/0333102419851810
Al-Hassany L, Goadsby PJ, Danser AHJ, MaassenVanDenBrink A (2022) Calcitonin gene-related peptide-targeting drugs for migraine: how pharmacology might inform treatment decisions. Lancet Neurol 21:284–294. https://doi.org/10.1016/S1474-4422(21)00409-9
D’Arco M, Giniatullin R, Simonetti M et al (2007) Neutralization of nerve growth factor induces plasticity of ATP-sensitive P2X<inf>3</inf> receptors of nociceptive trigeminal ganglion neurons. J Neurosci 27(31):8190–201. https://doi.org/10.1523/JNEUROSCI.0713-07.2007
Moraes BC, Ribeiro-Filho H v., Roldão AP, et al (2022) Structural analysis of TrkA mutations in patients with congenital insensitivity to pain reveals PLCγ as an analgesic drug target. Sci Signal 15. https://doi.org/10.1126/SCISIGNAL.ABM6046
Malerba F, Paoletti F, Bruni Ercole B, et al (2015) Functional Characterization of Human ProNGF and NGF Mutants: Identification of NGF P61SR100E as a “Painless” Lead Investigational Candidate for Therapeutic Applications. https://doi.org/10.1371/journal.pone.0136425
Buzzi MG, Tassorelli C, Nappi G (2003) Peripheral and central activation of trigeminal pain pathways in migraine: Data from experimental animal models. Cephalalgia Supplement 23:1–4. https://doi.org/10.1046/j.1468-2982.23.s1.1.x
Buzzi MG, Moskowitz MA (2005) The pathophysiology of migraine: year 2005. J Headache Pain 6:105–111. https://doi.org/10.1007/S10194-005-0165-2
Erdener ŞE, Kaya Z, Dalkara T (2021) Parenchymal neuroinflammatory signaling and dural neurogenic inflammation in migraine. J Headache Pain 22(1):138. https://doi.org/10.1186/s10194-021-01353-0
Franceschini A, Nair A, Bele T et al (2012) Functional crosstalk in culture between macrophages and trigeminal sensory neurons of a mouse genetic model of migraine. BMC Neurosci 13:143. https://doi.org/10.1186/1471-2202-13-143
Franceschini A, Hullugundi SK, van den Maagdenberg AMJM et al (2013) Effects of LPS on P2X3 receptors of trigeminal sensory neurons and macrophages from mice expressing the R192Q Cacna1a gene mutation of familial hemiplegic migraine-1. Purinergic Signal 9:7–13. https://doi.org/10.1007/s11302-012-9328-1
Bałkowiec-Iskra E, Vermehren-Schmaedick A, Balkowiec A (2011) Tumor necrosis factor-α increases brain-derived neurotrophic factor expression in trigeminal ganglion neurons in an activity-dependent manner. Neuroscience 180:322–333. https://doi.org/10.1016/J.NEUROSCIENCE.2011.02.028
Zhang XC, Kainz V, Burstein R, Levy D (2011) Tumor necrosis factor-α induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions. Pain 152:140–149. https://doi.org/10.1016/J.PAIN.2010.10.002
Bowen EJ, Schmidt TW, Firm CS et al (2006) Tumor necrosis factor-alpha stimulation of calcitonin gene-related peptide expression and secretion from rat trigeminal ganglion neurons. J Neurochem 96:65–77. https://doi.org/10.1111/J.1471-4159.2005.03524.X
Ferrari MD, Klever RR, Terwindt GM et al (2015) Migraine pathophysiology: lessons from mouse models and human genetics. Lancet Neurol 14:65–80. https://doi.org/10.1016/S1474-4422(14)70220-0
Ophoff RA, Terwindt GM, Vergouwe MN et al (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87:543–552. https://doi.org/10.1016/S0092-8674(00)81373-2
Tottene A, Conti R, Fabbro A et al (2009) Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in Ca(v)2.1 knockin migraine mice. Neuron 61:762–773. https://doi.org/10.1016/J.NEURON.2009.01.027
Chanda ML, Tuttle AH, Baran I et al (2013) Behavioral evidence for photophobia and stress-related ipsilateral head pain in transgenic Cacna1a mutant mice. Pain 154:1254–1262. https://doi.org/10.1016/J.PAIN.2013.03.038
Nair A, Simonetti M, Birsa N, et al (2010) Familial hemiplegic migraine CaV2.1 channel mutation R192Q enhances ATP-gated P2X3receptor activity of mouse sensory ganglion neurons mediating trigeminal pain. Mol Pain 6. https://doi.org/10.1186/1744-8069-6-48
Hullugundi SK, Ferrari MD, van den Maagdenberg AMJM, Nistri A (2013) The Mechanism of Functional Up-Regulation of P2X3 Receptors of Trigeminal Sensory Neurons in a Genetic Mouse Model of Familial Hemiplegic Migraine Type 1 (FHM-1). PLoS One 8:e60677. https://doi.org/10.1371/journal.pone.0060677
Hullugundi SK, Ansuini A, Ferrari MD et al (2014) A hyperexcitability phenotype in mouse trigeminal sensory neurons expressing the R192Q Cacna1a missense mutation of familial hemiplegic migraine type-1. Neuroscience 266:244–254. https://doi.org/10.1016/J.NEUROSCIENCE.2014.02.020
Fioretti B, Catacuzzeno L, Sforna L et al (2011) Trigeminal ganglion neuron subtype-specific alterations of Ca V2.1 calcium current and excitability in aCacna1amouse model of migraine. J Physiol 589:5879–5895. https://doi.org/10.1113/jphysiol.2011.220533
Chan KY, Labastida-Ramírez A, Ramírez-Rosas MB et al (2019) Trigeminovascular calcitonin gene-related peptide function in Cacna1a R192Q-mutated knock-in mice. J Cereb Blood Flow Metab 39:718–729. https://doi.org/10.1177/0271678X17725673
Gnanasekaran A, Bele T, Hullugundi S, et al (2013) Mutated CaV2.1 channels dysregulate CASK/P2X3 signaling in mouse trigeminal sensory neurons of R192Q Cacna1a knock-in mice. Mol Pain 9. https://doi.org/10.1186/1744-8069-9-62
Gnanasekaran A, Sundukova M, van den Maagdenberg AMJM et al (2011) Lipid rafts control P2X3 receptor distribution and function in trigeminal sensory neurons of a transgenic migraine mouse model. Mol Pain 7:77. https://doi.org/10.1186/1744-8069-7-77
Marchenkova A, Vilotti S, Fabbretti E, Nistri A (2015) Brain natriuretic peptide constitutively downregulates P2X3 receptors by controlling their phosphorylation state and membrane localization. Mol Pain 11:71. https://doi.org/10.1186/s12990-015-0074-6
Mehboob R, Marchenkova A, van den Maagdenberg AMJM, Nistri A (2021) Overexpressed Na V 1.7 Channels Confer Hyperexcitability to in vitro Trigeminal Sensory Neurons of Ca V 2.1 Mutant Hemiplegic Migraine Mice. Front Cell Neurosci 15:640709. https://doi.org/10.3389/fncel.2021.640709
Pietrobon D (2013) Calcium channels and migraine. Biochim Biophys Acta 1828:1655–1665. https://doi.org/10.1016/J.BBAMEM.2012.11.012
Indelicato E, Boesch S (2021) From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing. Front Neurol 12:639994. https://doi.org/10.3389/FNEUR.2021.639994
Mansoor SE, Lü W, Oosterheert W et al (2016) X-ray structures define human P2X 3 receptor gating cycle and antagonist action. Nature 538:66–71. https://doi.org/10.1038/nature19367
Giniatullin R, Nistri A (2013) Desensitization properties of P2X3 receptors shaping pain signaling. Front Cell Neurosci 7:245. https://doi.org/10.3389/fncel.2013.00245
Viatchenko-Karpinski V, Novosolova N, Ishchenko Y et al (2016) Stable, synthetic analogs of diadenosine tetraphosphate inhibit rat and human P2X3 receptors and inflammatory pain. Mol Pain 12:1744806916637704. https://doi.org/10.1177/1744806916637704
Ishchenko Y, Shakirzyanova A, Giniatullina R et al (2017) Selective calcium-dependent inhibition of ATP-gated P2X3 receptors by bisphosphonate-induced endogenous ATP analog APPPI. J Pharmacol Exp Ther 361(3):472–481. https://doi.org/10.1124/jpet.116.238840
Cook SP, McCleskey EW (1997) Desensitization, recovery and Ca2+-dependent modulation of ATP-gated P2X receptors in nociceptors. Neuropharmacology 36:1303–1308. https://doi.org/10.1016/S0028-3908(97)00132-9
Giniatullin R, Sokolova E, Nistri A (2003) Modulation of P2X<inf>3</inf> receptors by Mg2+ on rat DRG neurons in culture. Neuropharmacology 44. https://doi.org/10.1016/S0028-3908(02)00338-6
Maier JA, Pickering G, Giacomoni E et al (2020) Headaches and Magnesium: Mechanisms, Bioavailability, Therapeutic Efficacy and Potential Advantage of Magnesium Pidolate. Nutrients 12:1–14. https://doi.org/10.3390/NU12092660
Mauskop A, Varughese J (2012) Why all migraine patients should be treated with magnesium. J Neural Transm 119:575–579. https://doi.org/10.1007/s00702-012-0790-2
Pardutz A, Vecsei L (2012) Should magnesium be given to every migraineur? No. J Neural Transm (Vienna) 119:581–585. https://doi.org/10.1007/S00702-012-0791-1
Shatillo A, Salo RA, Giniatullin R, Gröhn OH (2015) Involvement of NMDA receptor subtypes in cortical spreading depression in rats assessed by fMRI. Neuropharmacology 93:164–70. https://doi.org/10.1016/j.neuropharm.2015.01.028
Somjen GG (2001) Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol Rev 81:1065–1096. https://doi.org/10.1152/PHYSREV.2001.81.3.1065
Guerrero-Toro C, Koroleva K, Ermakova E et al (2022) Testing the Role of Glutamate NMDA Receptors in Peripheral Trigeminal Nociception Implicated in Migraine Pain. Int J Mol Sci 23(3):1529. https://doi.org/10.3390/ijms23031529
Yin P, Anttila V, Siewert KM et al (2017) Serum calcium and risk of migraine: a Mendelian randomization study. Hum Mol Genet 26:820–828. https://doi.org/10.1093/HMG/DDW416
Khmyz V, Maximyuk O, Teslenko V et al (2008) P2X3 receptor gating near normal body temperature. Pflugers Arch 456:339–347. https://doi.org/10.1007/S00424-007-0376-2
Pryazhnikov E, Fayuk D, Niittykoski M et al (2011) Unusually strong temperature dependence of p2×3 receptor traffic to the plasma membrane. Front Cell Neurosci 5:27. https://doi.org/10.3389/fncel.2011.00027
Sacco S, Merki-Feld GS, Ægidius KL et al (2018) Effect of exogenous estrogens and progestogens on the course of migraine during reproductive age: A consensus statement by the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESCRH). J Headache Pain 19(1):76. https://doi.org/10.1186/s10194-018-0896-5
Vetvik KG, MacGregor EA (2017) Sex differences in the epidemiology, clinical features, and pathophysiology of migraine. Lancet Neurol 16:76. https://doi.org/10.1016/S1474-4422(16)30293-9
Nappi RE, Tiranini L, Sacco S et al (2022) Role of Estrogens in Menstrual Migraine. Cells 11(8):1355. https://doi.org/10.3390/CELLS11081355
MacGregor EA (2004) Oestrogen and attacks of migraine with and without aura. Lancet Neurol 3:354–361. https://doi.org/10.1016/S1474-4422(04)00768-9
Cho T, Chaban V v. (2012) Expression of P2X3 and TRPV1 receptors in primary sensory neurons from estrogen receptors-α and estrogen receptor-β knockout mice. Neuroreport 23:530–534. https://doi.org/10.1097/WNR.0b013e328353fabc
Seol SH, Chung G (2022) Estrogen-dependent regulation of transient receptor potential vanilloid 1 (TRPV1) and P2X purinoceptor 3 (P2X3): Implication in burning mouth syndrome. J Dent Sci 17:8–13. https://doi.org/10.1016/J.JDS.2021.06.007
Tobinaga H, Kameyama T, Asahi K, et al (2020) Pyrrolinone derivatives as a new class of P2X3 receptor antagonists. Part 3: Structure-activity relationships of pyrropyrazolone derivatives. Bioorg Med Chem Lett 30. https://doi.org/10.1016/j.bmcl.2020.127636
Obrecht AS, Urban N, Schaefer M et al (2019) Identification of aurintricarboxylic acid as a potent allosteric antagonist of P2X1 and P2X3 receptors. Neuropharmacology 158:107749. https://doi.org/10.1016/j.neuropharm.2019.107749
Kai H, Horiguchi T, Kameyama T et al (2021) Dioxotriazine derivatives as a new class of P2X3 receptor antagonists: Identification of a lead and initial SAR studies. Bioorg Med Chem Lett 37:127833. https://doi.org/10.1016/j.bmcl.2021.127833
Marucci G, Dal Ben D, Buccioni M et al (2019) Update on novel purinergic P2X3 and P2X2/3 receptor antagonists and their potential therapeutic applications. Expert Opin Ther Pat 29(12):943–963
Morice A, Smith JA, McGarvey L et al (2021) Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: A randomised, placebo-controlled, crossover phase 2a study. Eur Respir J 58(5):2004240. https://doi.org/10.1183/13993003.04240-2020
Garceau D, Chauret N (2019) BLU-5937: A selective P2X3 antagonist with potent anti-tussive effect and no taste alteration. Pulm Pharmacol Ther 56:56–62. https://doi.org/10.1016/j.pupt.2019.03.007
Richards D, Gever JR, Ford AP, Fountain SJ (2019) Action of MK-7264 (gefapixant) at human P2X3 and P2X2/3 receptors and in vivo efficacy in models of sensitisation. Br J Pharmacol 176:2279–2291. https://doi.org/10.1111/BPH.14677
Markham A (2022) Gefapixant: first approval. Drugs 82(6):691–695. https://doi.org/10.1007/s40265-022-01700-8
Garceau D, Chauret N (2019) BLU-5937: a selective P2X3 antagonist with potent anti-tussive effect and no taste alteration. Pulm Pharmacol Ther 56:56–62. https://doi.org/10.1016/j.pupt.2019.03.007
Ethics approval and consent to participate
Consent for publication
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Giniatullin, R., Nistri, A. Role of ATP in migraine mechanisms: focus on P2X3 receptors. J Headache Pain 24, 1 (2023). https://doi.org/10.1186/s10194-022-01535-4
- Trigeminal neurons