Sacral Nerve Modulation Alleviates Neuropathic Pelvic Pain Through Modulation of the Spinal Immune Microenvironment and Microglial Activation.

To investigate the efficacy of sacral neuromodulation (SNM) in alleviating neuropathic pelvic pain (NPP) and its underlying neuroimmune mechanisms, focusing on microglial activation and the CX3CL1-CX3CR1 pathway. A rat model of NPP was established via pelvic nerve crush (PNC), followed by SNM intervention. Pain behaviors were assessed using von Frey filaments and thermal withdrawal latency testing. Microglial activation, inflammatory factor expression, and signaling pathway dynamics in the spinal dorsal horn were analyzed using immunofluorescence, Western blot, qRT-PCR, and ELISA. Transcriptome sequencing was used to identify key pathways modulated by SNM. Exogenous CX3CL1, LPS, minocycline, and PLX5622 were employed to validate the roles of microglia and the CX3CL1-CX3CR1 axis in SNM-induced analgesia. PNC rats exhibited stable lower abdominal mechanical hypersensitivity, accompanied by significant microglial activation and increased expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in the spinal dorsal horn. SNM treatment ameliorated pain behaviors, suppressed microglial activation, reduced pro-inflammatory cytokine expression, and inhibited p38 and p65 phosphorylation. Transcriptome analysis revealed that SNM remodeled inflammation-related transcriptional profiles, notably suppressing the CX3CL1-CX3CR1 signaling axis. Exogenous CX3CL1 or LPS partially reversed SNM-induced analgesia and anti-inflammatory effects. Microglial depletion attenuated the PNC-induced pain phenotype, with no significant synergistic effect observed when combined with SNM. SNM alleviates NPP by inhibiting CX3CL1-CX3CR1-mediated microglial activation and downstream inflammatory signaling, thereby remodeling the spinal cord immune microenvironment. This study provides new evidence for the central immunological mechanism underlying SNM in treating chronic pelvic pain and suggests the CX3CL1-CX3CR1 axis as a potential target for combined neuromodulation therapy.