Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (on line): 1-10.

   

Sex-Dependent Mechanisms of Neuropathic Pain After Spinal Cord Injury Revealed by Integrated Transcriptomic and Metabolomic Profiling in Rats

Li Cheng1, #, Peihui Zhou2, #, Yijia Wang3, Xintong Zhu1, Yang Yang1, Bin Cai1, Hong Zeng1, 3, *, Li Wang2, *   

  1. 1Department of Rehabilitation Medicine, The Ninth People’s Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China; 2Department of Nephrology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 3Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China
  • Online:2025-01-01 Published:2025-10-28
  • Contact: Hong Zeng, zenghongxiezhen@163.com; Li Wang, wlyjy73122@126.com.
  • Supported by:
    This work was supported by grants from the National Natural Science Foundation of China (NSFC 82102644) to H.Z., the Shanghai Sailing Program (21YF1423900) to H.Z., the Shanghai Health Commission Key Supporting Discipline (2023ZDFC0303) to B.C., and the Hainan Provincial Natural Science Foundation High-level Talent Project (824RC558) to B.C.

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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