Trigeminal ganglion interferon-γ signaling drives orofacial neuropathic pain in rats

Chronic neuropathic pain, particularly in the orofacial region, markedly reduces quality of life. Peripheral trigeminal nerve injury activates satellite glial cells (SGCs) in the trigeminal ganglion (TG), which contributes to orofacial neuropathic pain. However, the upstream signal responsible for SGC activation remains unclear. This study investigated the role and cellular sources of interferon gamma (IFN-γ) signaling in the TG following infraorbital nerve injury (IONI) in rats.

Mechanical sensitivity of the whisker pad skin was assessed after IONI. Changes in IFN-γ levels, IFN-γ receptor expression, and glial fibrillary acidic protein (GFAP; a marker of SGC activation) were examined in the TG by immunohistochemistry. The effects of intra-TG administration of IFN-γ, an IFN-γ receptor antagonist, and isolated CD8⁺ T cells on mechanical hypersensitivity were evaluated. GFAP expression after intra-TG administration of IFN-γ or the receptor antagonist was also quantified. Flow cytometry and immunohistochemistry were used to identify IFN-γ-producing cells. In primary SGC cultures, IFN-γ-induced interleukin-1β (IL-1β) release was measured, and the impact of IL-1 receptor (IL-1R1) antagonism on mechanical hypersensitivity was tested. IL-1R1 localization and expression in TG neurons was further evaluated after IONI.

IONI induced persistent mechanical hypersensitivity and upregulated IFN-γ, IFN-γ receptor, and GFAP expression in the TG. CD8⁺ T cells were the primary source of IFN-γ after IONI, and intra-TG transfer of isolated CD8⁺ T cells transiently induced mechanical hypersensitivity. IFN-γ receptors were localized to SGCs, with expression levels increasing after IONI. Intra-TG IFN-γ administration triggered mechanical hypersensitivity and SGC activation, and its receptor antagonism attenuated the hypersensitivity. IFN-γ stimulation of cultured SGCs enhanced IL-1β release. Co-administration of an IL-1R1 antagonist prevented IFN-γ-induced mechanical hypersensitivity. IL-1R1 was localized on TG neurons and were upregulated following IONI.

CD8⁺ T cell-derived IFN-γ activates SGCs in the TG, leading to IL-1β release that promotes neuronal hyperactivity and orofacial neuropathic pain following IONI. Targeting the IFN-γ-SGC-IL-1β signaling axis may represent a novel therapeutic strategy for orofacial neuropathic pain.