Incision-triggered neuroimmune remodeling of nociceptor ion channels: from postoperative inflammation to pain chronification.

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-α, IL-1β, IL-6, chemokines, p38 MAPK, NF-κB, and gp130/JAK signaling. Direct incision evidence now includes antisense and pharmacologic studies linking TNF-α/p38/NF-κB 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-time-population alignment needed to determine whether this framework can guide mechanism-based prevention.