{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:51:33Z","timestamp":1790362293390,"version":"4.1.0"},"reference-count":170,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Chronic pain is a highly prevalent and disabling condition with a well-documented female predominance in incidence, severity and persistence. These sex differences are driven by sexually dimorphic neuroimmune mechanisms rather than psychosocial factors alone. This systematic review was conducted to comprehensively synthesize human clinical and translational evidence on sex-specific neuroimmune and glial cell pathways underlying chronic pain. Scientific literature was systematically searched from database inception to December 2025 across multiple biomedical databases to identify relevant clinical and translational studies. Across pain conditions, convergent evidence demonstrated that chronic pain mechanisms diverge by sex at cellular and molecular levels. Male-predominant pathways were characterized by microglial activation, particularly P2X4 receptor\u2013mediated signaling and brain-derived neurotrophic factor\u2013dependent neuronal disinhibition, supported by neuroimaging, transcriptomic, and pharmacological data. In contrast, female-predominant mechanisms involved adaptive immune processes, including CD4+ and CD8+ T cell infiltration, pannexin-1\u2013dependent leptin release, chemokine signaling, and astrocyte-mediated neuroimmune crosstalk. Sex-specific cytokine and chemokine profiles, differential glial activation patterns, and divergent neuroimmune\u2013endocrine interactions further distinguished pain pathways between males and females. Despite consistent mechanistic trends, substantial heterogeneity within each sex, limited sex-stratified power in many studies, and variability in outcome measures constrained quantitative synthesis and generalizability. The findings indicate that chronic pain is not a unitary disorder but rather a collection of mechanistically distinct conditions shaped by biological sex. These results highlight the limitations of sex-neutral therapeutic strategies and support the development of precision medicine approaches incorporating sex-informed neuroimmune biomarkers and mechanism-matched interventions. Future studies should prioritize adequately powered sex-stratified analyses, integration of neuroimmune biomarkers and clinical trial designs capable of detecting sex-by-treatment interactions.<\/jats:p>","DOI":"10.3390\/biom16020258","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T15:24:19Z","timestamp":1770305059000},"page":"258","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Sexually Dimorphic Neuroimmune Pathways in Chronic Pain: A Comprehensive Systematic Review of Cellular and Molecular Mechanisms"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3581-3584","authenticated-orcid":false,"given":"Nebojsa","family":"Brezic","sequence":"first","affiliation":[{"name":"Department of Medicine, NYCHH\/Lincoln, Bronx, NY 10451, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7260-5061","authenticated-orcid":false,"given":"Strahinja","family":"Gligorevic","sequence":"additional","affiliation":[{"name":"Department of Medicine, NYCHH\/Jacobi Medical Center\u2013North Central Bronx Hospital, Bronx, NY 10467, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9093-6998","authenticated-orcid":false,"given":"Aleksandar","family":"Si\u010d","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5651-7082","authenticated-orcid":false,"given":"Vasilis-Spyridon","family":"Tseriotis","sequence":"additional","affiliation":[{"name":"Department of Neurology, Agios Pavlos General Hospital of Thessaloniki, Leoforos Ethnikis Antistaseos 161, Kalamaria, 55134 Thessaloniki, Greece"},{"name":"Laboratory of Clinical Pharmacology, Aristotle University Campus, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8028-1495","authenticated-orcid":false,"given":"Nebojsa Nick","family":"Knezevic","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USA"},{"name":"Department of Anesthesiology, University of Illinois, Chicago, IL 60612, USA"},{"name":"Department of Surgery, University of Illinois, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1016\/S0140-6736(21)00393-7","article-title":"Chronic Pain: An Update on Burden, Best Practices, and New Advances","volume":"397","author":"Cohen","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.15585\/mmwr.mm6736a2","article-title":"Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults\u2014United States, 2016","volume":"67","author":"Dahlhamer","year":"2018","journal-title":"MMWR Morb. 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