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Immunol."],"abstract":"<jats:p>Chronic postsurgical pain (CPSP) arises after a known tissue insult, yet no intervention reliably prevents its development. This Review examines whether incision-triggered inflammation remodels nociceptor voltage-gated ion channels in ways that sustain peripheral input and favor pain chronification. We integrate human genetic and clinical evidence, incision-specific perturbation studies, functional work in non-surgical models, and expression-level associations distinguishing mechanistic strength from directness to CPSP. We focus on NaV1.7, NaV1.8, NaV1.9, and CaV3.2 within a broader network that includes peripheral transducing channels whose gating, trafficking, and abundance can be altered by TNF-\u03b1, IL-1\u03b2, IL-6, chemokines, p38 MAPK, NF-\u03baB, and gp130\/JAK signaling. Direct incision evidence now includes antisense and pharmacologic studies linking TNF-\u03b1\/p38\/NF-\u03baB signaling to NaV1.8 and NaV1.9 expression and acute hypersensitivity, as well as single-cell maps showing insult-specific macrophage and neutrophil programs and protective immune-derived signals. Evidence from rare channelopathies does not establish population-level CPSP susceptibility. However, no human study has demonstrated the complete sequence from a defined postoperative immune signal to altered channel function and persistent pain. Sex, age, and hormonal context are plausible modifiers, but the strongest mechanistic evidence remains model-dependent and preclinical. Selective NaV1.8 inhibition validates peripheral channel tractability for acute pain but not prevention of CPSP. We therefore propose a testable, evidence-calibrated framework in which pathogenic and resolving immune programs act across peripheral, ganglion, and spinal compartments, and we define the experiments, biomarkers, and target\u2013time\u2013population alignment needed to determine whether this framework can guide mechanism-based prevention.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1953337","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:53:15Z","timestamp":1791305595000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Incision-triggered neuroimmune remodeling of nociceptor ion channels: from postoperative inflammation to pain chronification"],"prefix":"10.3389","volume":"17","author":[{"given":"Xinye","family":"Song","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University","place":["Dalian, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University","place":["Dalian, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiachen","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University","place":["Dalian, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Luan","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University","place":["Dalian, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)68700-X","article-title":"Persistent postsurgical pain: risk factors and prevention","volume":"367","author":"Kehlet","year":"2006","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)30352-6","article-title":"Transition from acute to chronic pain after surgery","volume":"393","author":"Glare","year":"2019","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-12-04680.2000","article-title":"Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C","volume":"20","author":"Aley","year":"2000","journal-title":"J Neurosci"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2009.07.007","article-title":"Critical role 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