Early high-frequency spinal cord stimulation modulates the ROS/p38 MAPK/NF-κB and CXCL10/CXCR3 pathways to alleviate neuropathic pain and promote spinal cord injury repair
High-frequency spinal cord stimulation (HF-SCS) is an effective method for treating neuropathic pain (NP), but its specific mechanism of action in treating spinal cord injury (SCI) remains unclear. The present study aimed to explore the therapeutic effect of early HF-SCS in a rat model of SCI and its potential molecular mechanism. A Sprague-Dawley rat model of T10 spinal cord contusion was established and stimulation electrodes were implanted epidurally, which was followed by HF-SCS treatment (40% movement threshold at a frequency of 10 kHz). Through behavioral assessments, histopathological analysis and immunofluorescence staining, the present study demonstrated that HF-SCS markedly alleviated post-SCI NP, facilitated functional recovery and accelerated axonal regeneration and myelin repair. Mechanistic studies employing RNA sequencing, western blotting and immunofluorescence further revealed that HF-SCS exerted its neuroprotective effect by downregulating the reactive oxygen species/p38 MAPK/NF-κB signaling pathway to reduce microglial activation and decrease the release of proinflammatory factors; simultaneously, it inhibited the activation of the C-X-C motif chemokine ligand 10/C-X-C motif chemokine receptor 3 axis to alleviate central sensitization. These findings suggest that early HF-SCS intervention can improve the functional prognosis after SCI by suppressing neuroinflammation and reducing central sensitization, thereby providing a theoretical basis for the treatment of SCI with HF-SCS.