New insights into sex-specific visceral pain mechanisms

Pelvic pain is the most prevalent type of visceral pain, with high personal and societal costs. The objective of this study is to uncover the sensory ganglionic mechanisms of visceral hypersensitivity, which sustains peripheral afferent hyperactivity in chronic pelvic pain (CPP). To gain new insights into CPP mechanisms in the peripheral sensory nervous system, we first performed bulk-RNA transcriptome profiling in mouse lumbosacral dorsal root ganglia (DRG) receiving bladder afferents, following intravesical instillations of vascular endothelial growth factor (VEGF), which induces bladder pain. Our data revealed nearly non-overlapping gene activation/inactivation profiles in male and female lumbosacral DRG. Ingenuity Pathway Analysis (IPA), based in pain-associated differentially expressed genes (DEGs), suggested sex-specific signaling pathway activation associated with visceral hypersensitivity, with innate and adaptive immune activation in the female DRG and glia activation in male DRG. We next performed Translating Ribosome Affinity Purification (TRAP) followed by RNA sequencing (TRAP-seq) in satellite glial cells (SGCs) in the lumbosacral DRG. SGCs are the major type of glial cells in DRG and play important roles in controlling neuronal excitability and communicating with immune cells. Our data once again revealed significant sex differences in gene expression and signaling pathway changes associated with CPP symptoms. Importantly, the baseline SGC function might be sex-specific based on baseline enrichment of SGC translating mRNA profiles. Overall, our omics data highlighted that inflammatory processes are important in initiating and sustaining visceral pain in female mice, while nociceptive responses and glia-neuron communication might be driving male visceral pain. In addition, sensory neuron, Satellite glia, and immune cell interactions in lumbosacral DRG are likely to differ between sex in physiological conditions. Current study is focusing on the sex-specific DRG glial-immune interaction as well as glia-neuron interactions which could unlock therapeutic breakthroughs that target both sex-specific and sex-independent chronic pain. This study was supported by R01DK129260 to Xie. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.