TGF-β1 modulates PFC glial cell activation to facilitate exercise-induced analgesia in mice with spared nerve injury.

BACKGROUND: The prefrontal cortex (PFC) is a key brain region involved in pain-related processing. Exercise has been recognized as an effective non-pharmacological intervention for alleviating neuropathic pain; however, whether exercise exerts analgesic effects through modulation of the PFC and the underlying mechanisms remain unclear. This study aimed to investigate the role of the PFC in exercise-induced analgesia and to explore the potential involvement of TGF-β1 signaling and astrocyte activity. METHODS: A spared nerve injury (SNI)-induced neuropathic pain model was established in C57BL/6 J mice. Mice in the exercise group underwent low-intensity aerobic treadmill training (10 m/min, 30 min/day, no inclination). Mechanical and cold pain behaviors were assessed, and molecular and histological analyses of the PFC were performed. RESULTS: SNI led to foot after mechanical and cold pain hypersensitivity in mice (P < 0.01), reduce the expression of transforming growth factor - beta 1 (TGF-β1) (P < 0.01), increased astrocyte activation as indicated by elevated GFAP immunoreactivity (P < 0.01), and decreased the co-localization of TGF-β1 with astrocytes (P < 0.05). In SNI mice, exercise significantly attenuated pain hypersensitivity (P < 0.01), reduced astrocyte activation (P < 0.05), restored TGF-β1 expression (P < 0.01), and increased TGF-β1-astrocyte co-localization in the PFC (P < 0.05). Intrathecal administration of TGF-βR type â (TGF-βRâ ) receptor inhibitor attenuated exercise analgesia (P < 0.05), enhanced astrocyte activation (P < 0.01), and decreased TGF-β1 expression (P < 0.01). CONCLUSIONS: These findings suggest that aerobic exercise is associated with the restoration of TGF-β1/TGF-βRI signaling and attenuation of astrocyte activation in the PFC following peripheral nerve injury, which may contribute to exercise-induced analgesia. This study provides mechanistic insight into the role of PFC astrocytes and TGF-β1 signaling in the beneficial effects of exercise on neuropathic pain.