Liqiong He1,2 · Yu Zhang3  · Chunguang Yang1,2 · Zhifeng Huang1  · Kailu Zou1  · Qingwei Deng1  · Jianxi Zhang1  · Malijiang Mulati1  · Bei Sun1,2 · Qulian Guo1,2 · Changsheng Huang1,2

1 Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha 410000, China 

2 National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha 410000, China 

3 Department of Anesthesiology, Fujian Medical University Union Hospital, Fuzhou 350000, China

Abstract

The effective treatment of neuropathic pain continues to be a major clinical hurdle, largely because its pathogenic mechanisms are incompletely defined. This study identifies Fgr kinase as a central player in governing autophagy within spinal microglia during the development of neuropathic pain. Using a rat model of chronic constriction injury (CCI), we found that damage to peripheral nerves causes a prolonged increase in Fgr expression specifically in microglia of the spinal dorsal horn (SDH). Genetic interventions and behavioral analyses demonstrated that Fgr overexpression induced pain symptoms, whereas Fgr knockdown alleviated pain hypersensitivity. Mechanistically, Fgr directly phosphorylated STAT3, promoting its nuclear translocation and suppressing autophagic flux, evidenced by reduced LC3-II/LC3-I ratio, accumulated SQSTM1, and diminished autophagosomes. Pharmacological inhibition of Fgr by intrathecal TL02-59 (10 μg/kg) restored autophagy, attenuated STAT3 activation, and reversed CCI-induced neuropathic pain behaviors. These findings position the Fgr–STAT3 axis as a tractable target to normalize microglial autophagy and alleviate neuropathic pain.

Keywords

Neuropathic pain; Fgr kinase; STAT3 phosphorylation; Autophagy; Microglia

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