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

BACKGROUND: The prefrontal cortex (PFC) 1 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-1 signaling and astrocyte activity.METHODS: A spared nerve injury (SNI)-induced neuropathic pain model was established in C57BL/6J mice.Mice in the exercise group underwent low-intensity aerobic treadmill training (10 m/min, 30 min/day, no 1 PFC: prefrontal cortex; SNI: spared nerve injury; TGF-1: transforming growth factor -beta 1; TGF-R: TGF-R type J o u r n a l P r e -p r o o f 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-1) (P<0.01),increased astrocyte activation as indicated by elevated GFAP immunoreactivity (P<0.01), and decreased the co-localization of TGF-1 with astrocytes (P<0.05).In SNI mice, exercise significantly attenuated pain hypersensitivity (P<0.01),reduced astrocyte activation (P<0.05),restored TGF-1 expression (P<0.01), and increased TGF-1-astrocyte co-localization in the PFC (P<0.05).Intrathecal administration of TGF-R type (TGF-R) receptor inhibitor attenuated exercise analgesia (P<0.05),enhanced astrocyte activation (P<0.01), and decreased TGF-1 expression (P<0.01).CONCLUSIONS: These findings suggest that aerobic exercise is associated with the restoration of TGF-1/TGF-RI 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-1 signaling in the beneficial effects of exercise on neuropathic pain.