PACAP inhibition alleviates neuropathic pain by modulating Nav1.7 through the MAPK/ERK signaling pathway in a rat model of chronic constriction injury

Abstract

Background: Trigeminal neuralgia is a common chronic maxillofacial neuropathic pain disorder, and voltage-gated sodium channels (VSGCs) are likely involved in its pathology. Prior studies report that pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide highly expressed in the trigeminal ganglion, may contribute to dorsal root ganglion neuron excitability by modulating the Nav1.7.

Objective: We investigated whether PACAP can regulate Nav1.7 through the mitogen-activated protein kinase/ERK kinase/extracellular-signal-regulated kinase (MEK/ERK) pathway in the trigeminal ganglion after chronic constriction injury of the infraorbital nerve (ION-CCI) in rats.

Study design: Sprague-Dawley rats underwent ION-CCI, followed by intrathecal injection of PACAP 6-38 (PAC1 receptor antagonist) and PD98059 (MEK/ERK antagonist). Quantitative real-time PCR and western blot were used to quantify ATF3, PACAP, ERK, p-ERK, and Nav1.7 expression.

Results: The mechanical pain threshold decreased from day 3 to day 21 after ION-CCI and reached the lowest testing value by day 14; however, it increased after PACAP 6-38 and PD98059 injections. Additionally, ION-CCI surgery increased ATF3, PACAP, and p-ERK expression in the rat trigeminal ganglion and decreased Nav1.7 and PAC1 receptor expression; however, there was no difference in ERK expression. PACAP 6-38 injection significantly decreased PACAP, p-ERK, and Nav1.7 expression and increased the PAC1 receptor expression, with no change in ERK expression. Moreover, PD98059 injection decreased PACAP, p-ERK, and Nav1.7 expression and increased the expression of PAC1 receptor.

Conclusion: After ION-CCI, PACAP in the rat trigeminal ganglion can modulate Nav1.7 through the MEK/ERK pathway via the PAC1 receptor. Further, PACAP inhibition alleviates allodynia in ION-CCI rats.

Keywords: Infraorbital nerve chronic constriction injury(ION-CCI); Intrathecal injection; MAPK/ERK; Neuropathic pain; P-ERK; PAC1 receptor; Pituitary adenylate cyclase-activating polypeptide(PACAP); Trigeminal neuralgia; Volt-gated sodium channels(VGSCs).