Frontiers in molecular neuroscience · 2026
Tuina therapy alleviates neuropathic pain by modulating the CX3CL1/CX3CR1 axis to inhibit degradation of the perineuronal nets.
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Tian Yukui, Wang Cheng, Zhu Qingguang, Guo Lei, Bai Xue, Aikebaier Gulaisar, Cui Xiaofeng, Wu Zhiwei, Liu Junchang
Аннотация
INTRODUCTION: Tuina, a traditional Chinese non-pharmacological therapy, is effective in treating neuropathic pain (NP). However, its underlying molecular mechanisms remain elusive. The degradation of perineuronal nets (PNNs) via the CX3CL1/CX3CR1 axis is a key driver of central sensitization. This study investigates whether Tuina exerts analgesia by modulating this specific neuro-immune axis to preserve PNNs integrity in a rat model of chronic compression of the dorsal root ganglion (CCD).
METHODS: Sprague-Dawley rats were subjected to CCD surgery to establish the NP model. To validate the role of PNNs, a subset of rats received intrathecal chondroitinase ABC (chABC). To explore Tuina's mechanism, rats were divided into Sham, Model, Tuina, CX3CR1 inhibitor (AZD8797), and Tuina + AZD8797 groups. Standardized Tuina intervention or inhibitor administration was performed from days 4 to 14 post-surgery. Pain behaviors (PWT and PWL) were evaluated. Spinal dorsal horn tissues were analyzed using transmission electron microscopy, Western blotting, immunofluorescence, and flow cytometry.
RESULTS: CCD induced severe mechanical allodynia and thermal hyperalgesia, accompanied by the structural disruption of spinal PNNs-indicated by a significant loss of WFA-binding glycosaminoglycans despite unchanged total aggrecan core protein levels-and ultrastructural neuronal damage. Mechanistically, CCD upregulated the CX3CL1/CX3CR1/PI3K/AKT cascade, which was associated with increased markers of microglial phagocytosis (upregulated TREM2 and LAMP1), as well as Ca2+ influx and c-FOS accumulation. Tuina intervention attenuated these pathological alterations, significantly restoring WFA expression and suggesting a preservation of PNNs structural integrity. Furthermore, the combined treatment (Tuina + AZD8797) yielded an enhanced analgesic and biochemical recovery compared to either monotherapy.
CONCLUSION: Tuina produces robust central analgesia by suppressing the CX3CL1/CX3CR1-PI3K/AKT signaling pathway. This suppression restores microglial phagocytic homeostasis and crucially protects the glycosaminoglycan lattice of PNNs against excessive degradation, thereby alleviating neuropathic central sensitization.
METHODS: Sprague-Dawley rats were subjected to CCD surgery to establish the NP model. To validate the role of PNNs, a subset of rats received intrathecal chondroitinase ABC (chABC). To explore Tuina's mechanism, rats were divided into Sham, Model, Tuina, CX3CR1 inhibitor (AZD8797), and Tuina + AZD8797 groups. Standardized Tuina intervention or inhibitor administration was performed from days 4 to 14 post-surgery. Pain behaviors (PWT and PWL) were evaluated. Spinal dorsal horn tissues were analyzed using transmission electron microscopy, Western blotting, immunofluorescence, and flow cytometry.
RESULTS: CCD induced severe mechanical allodynia and thermal hyperalgesia, accompanied by the structural disruption of spinal PNNs-indicated by a significant loss of WFA-binding glycosaminoglycans despite unchanged total aggrecan core protein levels-and ultrastructural neuronal damage. Mechanistically, CCD upregulated the CX3CL1/CX3CR1/PI3K/AKT cascade, which was associated with increased markers of microglial phagocytosis (upregulated TREM2 and LAMP1), as well as Ca2+ influx and c-FOS accumulation. Tuina intervention attenuated these pathological alterations, significantly restoring WFA expression and suggesting a preservation of PNNs structural integrity. Furthermore, the combined treatment (Tuina + AZD8797) yielded an enhanced analgesic and biochemical recovery compared to either monotherapy.
CONCLUSION: Tuina produces robust central analgesia by suppressing the CX3CL1/CX3CR1-PI3K/AKT signaling pathway. This suppression restores microglial phagocytic homeostasis and crucially protects the glycosaminoglycan lattice of PNNs against excessive degradation, thereby alleviating neuropathic central sensitization.