Abstract: Neuropathic pain (NP) following spinal cord injury (SCI) is characterized by persistent spontaneous pain and evoked pain responses, such as mechanical allodynia and thermal hyperalgesia. Although inflammatory and metabolic reprogramming have been implicated in central sensitization, the sex-dependent molecular mechanisms underlying SCI-induced NP remain insufficiently understood. In this study, we established a T3 lateral hemisection SCI model in rats and assessed behavioral outcomes alongside integrated transcriptomic and metabolomic profiling. Both male and female rats developed significant mechanical and thermal hypersensitivity after SCI, confirming the induction of NP. 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 NP chronification after SCI. Our study highlights the importance of sex-dependent mechanisms in shaping neuroimmune and metabolic responses following SCI and provides novel insights into the molecular basis of central sensitization in NP.

Key words: Spinal cord injury, Neuropathic pain, Gender differences, Transcriptomics, Metabolomics