P2Y14 receptor in trigeminal ganglion contributes to neuropathic pain in mice

Abstract text (incl. figure legends and references)

Question: Trigeminal nerve injury usually induces trigeminal neuropathic pain but lacks effective treatments. Recent reports implied that P2Y14 receptor (P2Y₁₄R) activation promoted orofacial inflammatory pain and migraine. However, the role and mechanism of P2Y14R in trigeminal neuropathic pain remain unknown.

Methods: Trigeminal neuropathic pain was induced by chronic constriction injury of the infraorbital nerve (CCI-ION). Orofacial mechanical threshold was measured by Von-Frey tests. The ATF3 (a mark of nerve injury) and P2Y14R were detected by immunofluorescence in the trigeminal ganglion (TG). The P2Y₁₄R agonist (UDP-glucose) or antagonist (PPTN) was delivered by trigeminal ganglion injection in a stereotaxic apparatus. Furthermore, the expression of P2Y₁₄R and its potential downstream cellular signalings were measured by RT-qPCR and/or western blot (WB) in the TG.

Results: Firstly, CCI-ION induced orofacial mechanical hypersensitivity. The increased ATF3 expression in the TG confirmed trigeminal nerve injury. P2Y₁₄R was expressed in trigeminal ganglion neurons and satellite glial cells. RT-qPCR and WB showed that CCI-ION increased the expression of P2Y₁₄R, interleukin-1β, interleukin-6, C-C chemokine CCL2, and tumor necrosis factor-α in TG. Secondly, PPTN alleviated CCI-ION-induced mechanical hypersensitivity and proinflammatory cytokines production. UDP-glucose evoked orofacial mechanical hypersensitivity and upregulated proinflammatory cytokines above. Thirdly, phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 were increased in the TG after CCI-ION, which also were reduced by PPTN. Furthermore, the inhibitors of ERK1/2 (U0126) and p38 (SB203580) decreased these CCI-ION-induced proinflammatory cytokines.

Conclusions: The present study demonstrated that P2Y₁₄R in the TG contributed to trigeminal neuropathic pain via ERK- and p38-dependent neuroinflammation. P2Y₁₄R may be a potential drug target against trigeminal neuropathic pain.