Emerging Peripheral Receptor Targets for Deep-tissue Craniofacial Pain Therapies

Abstract

While effective therapies are available for some types of craniofacial pain, treatments for deeptissue craniofacial pain such as temporomandibular disorders are less efficacious. Several ion channels and receptors which are prominent in craniofacial nociceptive mechanisms have been identified on trigeminal primary afferent neurons. Many of these receptors and channels exhibit unusual distributions compared with extracranial regions. For example, expression of the ATP receptor P2X 3 is strongly implicated in nociception and is more abundant on trigeminal primary afferent neurons than analogous extracranial neurons, making them potentially productive targets specifically for craniofacial pain therapies. The initial part of this review therefore focuses on P2X 3 as a potential therapeutic target to treat deep-tissue craniofacial pain. In the trigeminal ganglion, P2X 3 receptors are often co-expressed with the nociceptive neuropeptides CGRP and SP. Therefore, we discuss the role of CGRP and SP in deep-tissue craniofacial pain and suggest that neuropeptide antagonists, which have shown promise for the treatment of migraine, may have wider therapeutic potential, including the treatment of deep-tissue craniofacial pain. P2X 3 , TRPV1, and ASIC3 are often co-expressed in trigeminal neurons, implying the formation of functional complexes that allow craniofacial nociceptive neurons to respond synergistically to altered ATP and pH in pain. Future therapeutics for craniofacial pain thus might be more efficacious if targeted at combinations of P2X 3 , CGRP, TRPV1, and ASIC3.

Nociceptin/orphanin FQ up‐regulates P2X3 receptors in primary cultures of neonatal rat trigeminal ganglion neurons

“…Most of these co‐expressing cells were small‐ to medium‐sized neurons. As previously reported, whilst P2X 3 ‐positive neurons in dorsal root ganglia rarely express neuropeptides, extensive co‐expression of P2X 3 and neuropeptides is found in TG neurons, suggesting a far greater interaction between neuropeptides and P2X 3 in craniofacial pain . Recent studies have already demonstrated the stimulating effects of Substance P and CGRP on P2X 3 receptor .…”

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

“…Although a central origin of migraine attacks has been proposed, it seems likely that the acute onset of headache is at least partly due to sensitization of trigeminal sensory neurons [1][2][3], the large majority of which are activated by extracellular adenosine-5′-triphosphate (ATP) via purinergic ionotropic receptor 3 (P2X3)-sensitive receptors [4][5][6]. Trigeminal ganglion sensory neurons of a transgenic mouse model (i.e., R192Q knockin (KI)) expressing the R192Q missense mutation in the α1 subunit of the P/Q-type Ca 2+ channel that is encoded by the Cacna1a gene [7], and which causes human familial migraine type-1 (FHM-1), show functional upregulation of P2X3 receptors under basal conditions consistent with their constitutive sensitization [8].…”

Eccentric muscle contraction and stretching evoke mechanical hyperalgesia and modulate CGRP and P2X3 expression in a functionally relevant manner

“…Thus muscle damage, subsequent inflammation and increased primary afferent drive could initiate or exacerbate chronic craniofacial pain. A high percentage of craniofacial deep tissue primary afferent neurons also express the P2X 3 receptor and co-localize CGRP with P2X 3 [2]. …”