Identification of Genes for Improving Cold Sensitivity in Nerve-Damaged Rats Via Lumbar Sympathectomy Using Poly(A)-seq.

Abstract

Background: Lumbar sympathectomy improves blood flow to the lower limbs and is widely used in clinical practice to treat lower limb pain and cold. However, the therapeutic mechanisms underlying lumbar sympathectomy for limb coldness resulting from nerve injury remain unclear. This study aimed to investigate the effect of lumbar sympathectomy on cold allodynia in rats with spared nerve injury (SNI) and identify potential target genes associated with its analgesic effects.

Methods: A rat model of SNI was established. Mechanical and cold pain thresholds were assessed in rats with SNI to explore the analgesic effects of lumbar sympathetic neurectomy on cold allodynia. Poly(A)-seq was used to analyze the transcriptional profile of the spinal cord. Differentially expressed genes (DEGs) were screened and analyzed using bioinformatics and validated by quantitative PCR analysis.

Results: Lumbar sympathectomy improved mechanical pain, cold allodynia, and cold sensitivity in the ipsilateral hind paw of SNI rats (all p < 0.05). Poly(A)-seq identified 278 DEGs (177 upregulated and 101 downregulated) in the spinal cords of SNI model rats compared with control rats. We identified 174 DEGs in the gene expression profile of lumbar sympathectomized SNI rats, including 69 upregulated and 105 downregulated genes, compared with SNI model rats. Functional analysis of the DEGs revealed that the most significantly enriched pathways included immune-related pathways and cellular molecular components, which mediate neuroinflammation, central sensitization, and chronic pain. To explore the correlation among the DEGs, we used the STRING database to construct protein-protein interaction networks. Finally, quantitative PCR analysis revealed six potential target genes associated with cold analgesic effects epithelial mitogen gene (EPGN), histone cluster 2 H3 family member C2 (Hist2h3c2), small integral membrane protein 6 (Smim6), family with sequence similarity 187 member a (FAM187A), LOC108349650, and LOC102550818.

Conclusions: Lumbar sympathectomy may alleviate cold allodynia in SNI model rats. We identified key genes associated with pain mitigation, offering potential therapeutic targets. These genes may serve as targets for treating nerve injury-induced cold allodynia. These findings provide valuable insights for the development of new treatments for nerve-related pain disorders.