Abstract

Trigeminal neuralgia is a debilitating neuropathic pain disorder characterized by facial hypersensitivity, yet its underlying molecular mechanisms remain incompletely understood. Using a mouse model of partial infraorbital nerve transection (pT-ION), we investigated transcriptomic alterations in the trigeminal ganglion (TG) to identify molecular contributors to orofacial pain. Microarray analysis identified 200 differentially expressed genes, with functional enrichment highlighting immune-related processes, calcium signaling, and lysosomal pathways. Among these, Calb2 (calretinin) emerged as a hub gene in both coexpression and protein-protein interaction networks. Immunofluorescence analysis revealed prominent colocalization of calretinin with the voltage-gated calcium channel auxiliary subunit α2δ1 (Cavα2δ1) in TG neurons. Functionally, a single perineural injection of calretinin siRNA into the trigeminal nerve significantly alleviated mechanical and cold hypersensitivity in both the maxillary and mandibular facial regions within 48 h. Pharmacological inhibition of Cavα2δ1 with gabapentin similarly attenuated pain behaviors and reduced calretinin expression in the TG. Conversely, targeted overexpression of Cavα2δ1 in naïve mice was sufficient to induce orofacial hypersensitivity and to upregulate calretinin expression in the TG. Together, these findings identify calretinin as a key downstream contributor to Cavα2δ1-associated trigeminal pain signaling and suggest that modulation of the Cavα2δ1-calretinin axis may represent a potential therapeutic strategy for trigeminal neuropathic pain.