Peripheral sensitization in migraine—role for P2X purinergic receptors in the dura–vascular sensory pathway

Abstract

Peripheral sensitization is still considered a prime contributor underlying the mechanisms of migraine. Trigeminal primary afferent neurons are the first neurons in the dural nociceptive pathway, and activation results in conscious perception of pain. Peripheral sensitization can lower the activation threshold of primary afferent neurons, rendering them more excitable, allowing for increases in release of neurotransmitter from both central and peripheral terminals. Increase in neurotransmitter release from central terminals contributes to excitation of second-order neurons, while the release of peptides from peripheral terminals has been implicated in neurogenic inflammation. Adenosine 5 0 -triphosphate (ATP) causes pain in human studies, and depolarize sensory neurons. There is evidence of the action of ATP at many levels in the dura-vascular sensory pathway. Animal studies have shown that some P2X receptors are located in neurons innervating the dura, including the P2X 3 receptor, which is most often shown to be involved in nociceptive pathways. In this article, we briefly review peripheral sensitization in relation to migraine and provide emphasis for P2X receptor involvement where it is available. Drug Dev Res 68: 321-328, 2007. r 2007 Wiley-Liss, Inc.

Purinergic Receptors and Pain

“…The interaction of P2Y 1 receptors on trigeminal neurons with P2X 3 receptors after sensitisation of these neurons with algogenic stimuli (e.g., NGF, BDNF or bradykinin) has been proposed and may also represent a new potential target for antimigraine drugs [241]. Peripheral sensitisation is considered as a contributor to mechanisms underlying migraine headache and a recent review concludes that ATP has a role in sensitisation of primary afferents at both peripheral and central terminals [242].…”

Peripheral Nervous System

“…The hypothesis gained further support by the identification of P2X 3 receptors on primary afferent nerve terminals supplying cerebral vessels arising from trigeminal, nodose and spinal ganglia (Chen et al 1995a;Burnstock 1996cBurnstock , 2001b. A role for P2X 3 receptors in peripheral sensitisation in the dura-vascular sensory pathway in migraine has been described (Jennings and Cho 2007). Thus, P2X 3 receptor antagonists may be candidates for antimigraine drug development (Waeber and Moskowitz 2003).…”

Dental Pain: Is ATP the key mediator?

“…There has been particular interest in P2X 3 containing receptors in the trigeminal system as these receptors are found predominantly on small diameter nociceptive sensory neurons [12][13][14][15][16][17]. In addition, other key P2X receptor subtypes that have attracted interest in the trigeminal system include P2X 1, P2X2 and P2X4 [14][15][16][17]. One Dental pain has a significant impact on the population and presently its poorly described mechanisms limits its effective therapeutic management in patients.…”

“…Recently, chaperone proteins like sigma-1 receptors have been shown to facilitate the P2X receptor mediated mechanical allodynia [35] further contributing to understand the underlying mechanism behind ATP signaling in mechanical sensitivity. In trigeminal sensory neurons innervating the dura, it has been shown that ATP is released from a range of cell types including smooth muscles and endothelial cells [36], and that this ATP contributes to peripheral sensitization in trigeminal sensory neurons during migraine [14,36,37].…”