Sex and Gender Dependent Mechanisms of Pain

Chronic pain conditions, including fibromyalgia, migraine, temporomandibular disorders, and neuropathic pain, affect women at roughly twice the rate of men, yet the mechanistic basis for this disparity has only recently become a serious focus of preclinical and clinical investigation. Over the past decade, the discovery that spinal microglial activation drives pain hypersensitivity in male rodents while T-cell-dependent adaptive immune responses dominate in females has forced a fundamental reappraisal of how we model pain and, by extension, how we design treatments. Layered onto this are the dynamic effects of gonadal and stress hormones across the lifespan, from puberty through menopause and andropause, and growing evidence that X-chromosome dosage and X-linked gene expression in dorsal root ganglia neurons contribute to baseline differences in nociceptive threshold and sensitization. What was once attributed to psychology or reporting bias is increasingly traceable to discrete, targetable biology.The field now faces a set of problems that require coordinated mechanistic work across scales and model systems. How do estrogen, progesterone, and testosterone act on peripheral nociceptors, spinal interneurons, and descending modulatory circuits to produce divergent pain phenotypes? What is the functional relationship between sex-specific immune cell recruitment and central sensitization? How do sex-stratified transcriptomic and proteomic profiles in DRG and dorsal horn translate into differences in temporal and spatial summation, conditioned pain modulation, and endogenous opioid tone? And how should experimental and clinical paradigms be redesigned to generate data that are actually powered to detect sex-dependent effects? This Research Topic welcomes mechanistic studies, computational models, and translational frameworks that address these questions directly, including work on sex-divergent glial signaling, gonadal hormone receptor function in nociceptive pathways, stress-hormone crosstalk with central sensitization, and the design of sex-balanced preclinical and clinical protocols.Contributions may take the form of original research articles, systematic reviews, or methods papers. Relevant thematic areas include microglial and astrocytic sex dimorphism in the spinal dorsal horn, neuroendocrine regulation of peripheral and central sensitization, X-linked ion channel and receptor expression in sensory neurons, sex-stratified single-cell and spatial transcriptomics, hormonal fluctuation across the lifespan and its relationship to pain chronification, and the intersection of gender-related psychosocial factors with biological pain mechanisms. Both preclinical and clinical mechanism studies are welcome, as are human experimental pain paradigms that incorporate hormonal status and sex as primary variables rather than covariates. The goal is to build a coherent mechanistic picture of how sex and gender shape pain from the periphery to the cortex, one that directly informs the next generation of targeted therapies. Topic editors: Paramita Basu, Aubin Moutal Source: https://www.frontiersin.org/research-topics/83231/sex-and-gender-dependent-mechanisms-of-pain