Histamine Upregulates Nav1.8 Expression In Primary Afferent Neurons Via H2 Receptor:Involvement In Neuropathic Pain

Abstract:Objective:Currently it is considered that the upregulation of Nav1.8 expressed on the primary sensory neurons (DRG neurons) plays an important role in the development of neuropathic pain. As an inflammatory mediator and chemokine, histamine is involved in the regulation of pain. This experiment was designed to study whether histamine participates in regulating the expression of Nav1.8 on the primary sensory neurons, and further explored its role in the development of neuropathic pain.Methods and Results:[1] Histamine significantly increased the expression of Navl.8 in cultured DRG neurons, which was reversed by H2 receptor antagonist cimetidine or famotidine, but not by H1 receptor antagonist pyrilamine. [2] Peri-sciatic administration of histamine induced upregulation of Nav1.8 expression in primary afferent neurons and behavioral hypersensitivity in the hindpaw. Famotidine, but not pyrilamine, inhibited the upregulation of Navl.8 expression, and attenuated the mechanical allodynia and to less extent, thermal hyperalgesia. [3] Famotidine administered through postoperative days significantly suppressed the progression of autotomy and delayed the onset day of pain in the neuroma model. Moreover,.compared with the saline-treated group, the mechanical allodynia and thermal hyperalgesia in the famotidine group were significantly attenuated in the PSL model. Meanwhile, famotidine inhibited Nav1.8 overexpression in the sciatic nerve in both models.Conclusions:Our findings indicate that histamine increases Nav1.8 expression in primary afferent neurons via H2 receptor-mediated pathway and thereby contributes to neuropathic pain. H2 receptor antagonists may be potentially used as analgesics for patients with neuropathic pain.