Role of ATP in migraine mechanisms: focus on P2X3 receptors

Abstract

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.

Effects of Nitric Oxide on the Activity of P2X and TRPV1 Receptors in Rat Meningeal Afferents of the Trigeminal Nerve

“…According to the purinergic theory of migraine, ATP, on the one side, mediates the vascular changes during a migraine attack [58]. On the other side, ATP stimulates directly the primary afferents located along the cerebral vessels through P2X3 receptors, which are expressed both in the afferent endings and in the trigeminal ganglion neurons [17,25,27,[59][60][61][62]. In addition, the pro-nociceptive effect of ATP is aggravated by the degranulation of meningeal mast cells followed by the release of serotonin, which has its own neuronal effects through 5-HT3 receptors [25,61,63,64].…”

“…On the other side, ATP stimulates directly the primary afferents located along the cerebral vessels through P2X3 receptors, which are expressed both in the afferent endings and in the trigeminal ganglion neurons [17,25,27,[59][60][61][62]. In addition, the pro-nociceptive effect of ATP is aggravated by the degranulation of meningeal mast cells followed by the release of serotonin, which has its own neuronal effects through 5-HT3 receptors [25,61,63,64]. The interaction among P2X3 receptors, CGRP, and NO was proposed in migraine-associated signaling cascades [15].…”

“…Purinergic P2X receptors are widely expressed in meningeal tissues [17,22,23], and numerous data confirm their involvement in nociception [24][25][26][27]. The interplay of purinergic receptors (P2X and P2Y) and NO is described for a number of structures, such as the hypothalamus, brain stem, and vascular endothelium.…”

Novel Therapeutic Targets for Migraine

“…Adenosine has been widely studied in the cardiovascular system, as it causes vasodilation through A 2A receptors, whereas in the atrioventricular and sinoatrial nodes, it binds with the A 1 receptor, reducing heart rate. Adenosine may also play a role in migraine pathogenesis as a part of the breakdown product of adenosine triphosphate (ATP) and its binding to ATP-gated P2X3 receptors [30].…”

Autophagy may protect the brain against prolonged consequences of headache attacks: A narrative/hypothesis review

“…The trigeminal nerve terminals must be depolarized before generating nociceptive signaling 60 . That depolarization can be induced by various stimuli, including ATP, which seems to have a special position among them as it is a potent pain inducer and is involved in many effects directly or indirectly related to migraine (reviewed in Giniatullin and Nistri 61 ). Extracellular ATP is bound in CNS by ionotropic P2X or metabotropic P2Y receptors 62 .…”