Transcriptome profiling suggests molecular sexual dimorphism in lumbosacral dorsal root ganglia and sex-specific mechanisms underlying visceral pain

Dorsal root ganglia (DRG) are essential for transmitting sensory information from visceral organs to the central nervous system. Sensory neuronal hyperactivity and glial reactivity have been reported in DRG in animal models of chronic pain, yet the molecular mechanisms contributing to the pathogenesis of visceral pain remain unclear. In this study, we performed transcriptome profiling of lumbosacral DRG in a mouse model of chronic pelvic pain, focusing on mapping the gene and signaling pathway changes associated with visceral hypersensitivity in lumbosacral DRG transmitting bladder afferent signals. Using the bulk RNA-sequencing method, we identified differentially expressed genes in the lumbosacral DRG between control mice and mice exhibiting visceral pain symptoms, with striking sex differences in identified genes. Hierarchical gene clustering analysis and Ingenuity Pathways Analysis both revealed sex-specific signaling pathway activation associated with visceral pain conditions, including glial activation and nociceptive sensitization in males and heightened immune activation in females. Interestingly, our data also showed enriched gene expression linked to extracellular matrix and immune functions in female control animals compared with male control animals, suggesting molecular sexual dimorphism in sensory ganglia. Finally, our data identified common genes and signaling pathway changes involved in visceral hypersensitivity in both sexes. This study is the first molecular and signaling pathway characterization in the lumbosacral DRG in the context of bladder-origin visceral pain. The sex differences in the molecular profile of lumbosacral DRG in healthy animals and in animals exhibiting visceral pain symptoms suggest sex-specific visceral pain etiology, despite similar symptoms.<b>NEW & NOTEWORTHY</b> This study examined transcriptomics in the lumbosacral DRG in a VEGF-induced visceral pain mouse model. Male and female mice underwent intravesical instillations of VEGF₁₆₅ or saline. Across the four experimental groups, we found significant sex differences in DRG transcriptome between control animals and VEGF-induced molecular changes, suggesting sex-specific visceral pain mechanisms. These findings provide insight into potential targets for alleviating visceral pain symptoms when considering sex as a biological variable.