Sex as a Biological Variable in Molecular Pain Mechanisms

Sex differences in the prevalence, severity, and disability associated with pain are well documented in both clinical and preclinical research. Despite this, the precise molecular mechanisms underlying these differences, as well as the neuromodulators that shape them, remain incompletely understood. Emerging evidence indicates that components of the peripheral nervous system may contribute to these sex-dependent differences in pain processing. Sensory neurons, Schwann cells, and satellite glia, as well as resident or infiltrating immune cells, exhibit sex-dependent differences in excitability and in their response to injury or inflammation. In addition, sex hormones have been shown to modulate nociceptive signaling. These observations are further supported by the marked sex differences observed across pain conditions, such as migraine and neuropathic pain. Together, these findings underscore the importance of including biological sex as a variable when investigating the molecular mechanisms and neuromodulators involved in the pathophysiology of pain disorders, as well as their role in treatment outcomes.This Research Topic aims to advance our understanding of how biological sex influences the molecular mechanisms underlying pain. A major challenge in the field is that sex differences are often described at the behavioral or epidemiological level without clear mapping to specific cell types and signaling pathways. This gap limits the development of mechanistically informed, precision therapies, tailored to individual biological differences. This collection therefore seeks to clarify how sex-dependent mechanisms contribute to pain signaling and to identify potential targets for more effective and personalized pain treatments.We welcome contributions that (i) identify sex-dependent molecular and cellular interactions among nociceptors, glial populations, and immune cells; (ii) elucidate how hormonal, genetic, and epigenetic factors shape these interactions; and (iii) determine how such mechanisms contribute to disability, resilience, and disease progression across pain conditions. We also encourage work addressing sex- and gender-dependent therapeutic responses, including mechanisms underlying variability in efficacy, tolerance, and adverse effects across established and emerging therapies. Themes of interest include, but are not limited to:• Sex-dependent nociceptor signaling: modulation of excitability; ion channels (e.g., Nav1.7/Nav1.8, TRPV1, ASICs); GPCR pathways; second-messenger cascades.• Neuroimmune mechanisms in PNS and CNS: macrophages, mast cells, neutrophils and other immune populations; cytokines/chemokines; complement; bidirectional immune–neural signaling.• Glial contributions: Schwann cells and satellite glia; myelination/demyelination; neurotrophin signaling; glia–axon communication in injury and repair.• Mechanistic studies in specific disorders: headache and migraine, neuropathic pain, visceral pain, inflammatory pain, and related sex-biased pain phenotypes.• Hormonal modulation: estradiol, progesterone, and testosterone effects on neuronal and immune function; hormone–tissue interactions shaping sensitization and resolution.• Genetic and epigenetic regulation: sex chromosome effects, imprinting, DNA methylation, miRNAs and other noncoding RNAs; transcriptional and post-transcriptional control of pain pathways.• Sex-dependent analgesic responsiveness: molecular bases of differences in therapeutic efficacy, tolerance, and side-effect profiles across pharmacological and non-pharmacological interventions.• Tissue context: skin, joint, gut/viscera; injury/repair; inflammation-driven sensitization• Methods emphasis: single-cell and spatial omics; human iPSC-derived sensory neurons and glial/immune co-cultures; patient-derived samples/biopsies; multimodal phenotyping and translational model systems. Topic editors: Eloisa Rubio-Beltran, Álvaro Llorente-Berzal, Kimberly Gomez Source: https://www.frontiersin.org/research-topics/79079/sex-as-a-biological-variable-in-molecular-pain-mechanisms