TRPM3 mediates spontaneous pain and mechanical allodynia in a mouse model of chronic orofacial neuropathy.

Abstract

Trigeminal nerve injury can lead to chronic and difficult-to-treat orofacial neuropathic pain. Here, we uncover a key role for the cation channel TRPM3 in the chronic constriction injury of the infraorbital nerve (IoN-CCI) mouse model of trigeminal neuropathic pain. Wild-type (WT) mice develop spontaneous pain and mechanical allodynia for up to 6 weeks following IoN-CCI, whereas Trpm3^-/- mice do not develop such symptoms. Using longitudinal RNA sequencing (RNA-seq) analysis, we obtain a detailed time course of transcriptome alterations in trigeminal ganglia during progression of the IoN-CCI model; notably, gene expression regulation is not different between WT and Trpm3^-/- mice. Two structurally distinct TRPM3 antagonists, primidone and isosakuranetin, effectively reverse spontaneous pain and mechanical allodynia, whereas mavatrep, a potent TRPV1 antagonist, is without analgesic effect. These data indicate that TRPM3 is essential for ongoing pain and allodynia following trigeminal nerve injury, making it a potential target for treating trigeminally mediated neuropathic pain.