Sex-dependent mechanisms of neuropathic pain after spinal cord injury in rats: An integrated analysis based on transcriptomic and metabolomic profiling

Neuropathic pain following spinal cord injury is characterized by persistent spontaneous pain and evoked pain responses, such as mechanical allodynia and thermal hyperalgesia. Although inflammatory and metabolic reprogramming has been implicated in central sensitization, the sex-dependent molecular mechanisms underlying spinal cord injury-induced neuropathic pain remain insufficiently understood. Therefore, this study used an integrated analysis of transcriptomics and metabolomics to investigate the mechanisms underlying sex differences in neuropathic pain after spinal cord injury in rats. We established a rat model of T3 lateral hemisection spinal cord injury and assessed behavioral outcomes on the basis of integrated transcriptomic and metabolomic profiling. Both male and female rats developed significant mechanical and thermal hypersensitivity after spinal cord injury, confirming successful induction of neuropathic pain. However, unbiased multi-omics analyses revealed distinct sex-dependent molecular programs. Male rats exhibited alterations in calcium signaling, serine metabolism, and sphingolipid metabolic pathways, whereas female rats showed prominent changes in T cell receptor signaling and histidine metabolism. These findings suggest that immune-metabolic interactions diverge between sexes and may underlie the observed differences in spontaneous pain chronification after spinal cord injury. Our study highlights the importance of sex-dependent mechanisms in shaping neuroimmune and metabolic responses following spinal cord injury and provides novel insights into the molecular basis of central sensitization in spontaneous pain.