Inhibition of spinal astrocytic GPR177 attenuates neuropathic pain by modulating C3/C3aR signaling in male rats

Neuropathic pain (NP) remains refractory to conventional therapy partly because its pathogenesis is incompletely understood. G protein-coupled receptor 177 (GPR177), a multi-pass transmembrane protein, regulates Wnt trafficking and secretion. Here, we use a chronic constriction injury model in male rats and find GPR177 predominantly expresses in spinal astrocytes and co-localizes with complement component 3 (C3). During NP development, astrocytic GPR177 expression increases, accompanied by activation of C3/C3a receptor (C3aR) signaling in the spinal dorsal horn. Gpr177 silencing with siRNA alleviates nerve injury-associated hypersensitivity and reduces the increases in GPR177, glial fibrillary acidic protein, C3, and C3aR. Intrathecal administration of the C3 inhibitor compstatin and the C3aR antagonist SB290157 reduces hypersensitivity and suppresses C3/C3aR activation, supporting the involvement of C3/C3aR signaling in NP development. These findings demonstrate that spinal GPR177 contributes to NP by activating astrocytes and regulating the C3/C3aR signaling pathway, suggesting the GPR177/C3/C3aR axis as a potential therapeutic target for NP.