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. This work was supported by the Natural Science Foundation of Zhejiang Province, China (LR23C090001), National Natural Science Foundation of China (32071019), and Science and Technology Innovation Program of China-2030 (2021ZD0200408). These authors contributed equally: Hui Zhang, Meng-Jing Yang.

Department of Anesthesia, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China Hui Zhang, Meng-Jing Yang, Ang Li, Yu-Fan Liu, Kai Guo & Yong-Xing Yao Nanhu Brain–Computer Interface Institute, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, Hangzhou, China Centre for Neuroscience, Zhejiang University School of Medicine, Hangzhou, China The authors declare that they have no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material.

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To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. Zhang, H., Yang, MJ., Li, A. et al. Inhibition of spinal astrocytic GPR177 attenuates neuropathic pain by modulating C3/C3aR signaling in male rats.