Microglia-mediated neuroinflammation and demyelination contribute to pain and social behavioral deficits after spared nerve injury.

Neuropathic pain (NPP) is increasingly recognized as a multidimensional disorder characterized not only by sensory hypersensitivity but also by affective and social dysfunction. However, the cellular mechanisms linking peripheral nerve injury to higher-order behavioral abnormalities remain poorly understood. Using a spared nerve injury (SNI) mouse model, we investigated whether microglia-driven neuroinflammation and demyelination contribute to pain hypersensitivity and social behavioral deficits. SNI induced persistent mechanical allodynia and thermal hyperalgesia, accompanied by a selective impairment in social novelty preference while basic sociability remained intact. At the cellular level, SNI triggered robust activation of spinal microglia and astrocytes, together with a pro-inflammatory shift characterized by elevated TNF-α and IL-1β and reduced anti-inflammatory cytokine IL-10. Concomitantly, a significant loss of CC1-positive mature oligodendrocytes and disruption of myelin integrity were observed in both the spinal cord (SC) and the anterior cingulate cortex (ACC), a key region involved in pain affect and social behavior. Importantly, pharmacological ablation of microglia via intraperitoneal administration of the CSF1R inhibitor PLX5622 markedly alleviated pain hypersensitivity, restored social novelty behavior, and rescued demyelination in both regions. Together, these findings identify microglia-driven central demyelination as a critical pathological mechanism linking peripheral nerve injury to sensory and social dysfunction, and highlight microglia-oligodendrocyte-myelin interactions as potential therapeutic targets for chronic pain.