Sex-Specific Mechanisms of Central Sensitization: A Narrative Review of the Neuroimmune Architecture of Chronic Pain

Chronic pain disproportionately affects women, yet analgesic development has been built predominantly on male biological substrates, reflecting a now-refuted assumption of biological symmetry that excluded female subjects from preclinical investigation. Central sensitization, the pathological amplification of central nervous system signalling that produces pain hypersensitivity, is increasingly recognized as a sex-dependent neuroimmune phenomenon with distinct cellular and molecular signatures in males and females. This narrative review, prepared in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA), synthesizes evidence challenging the "one-size-fits-all" paradigm and proposes a transition toward biological-sex-informed precision analgesia. In males, central sensitization is predominantly mediated by spinal microglial activation via the P2X4 receptor-brain-derived neurotrophic factor (BDNF) axis, culminating in potassium-chloride cotransporter type 2 (KCC2) downregulation and GABAergic disinhibition. In females, it proceeds through spinal T-lymphocyte infiltration and direct pro-excitatory actions of interferon-γ and tumor necrosis factor-α on dorsal horn neurons, a pathway largely refractory to microglial-targeted intervention. Gonadal steroids act as neuroimmune modulators: 17β-estradiol amplifies central excitability, whereas testosterone is antinociceptive. Epigenetic mechanisms consolidate these signals into durable transcriptional programs that sustain sensitization after injury resolves. The failure of microglial-targeted therapies in female-predominant cohorts reflects a sex-mismatched strategy. Inclusion of biological sex as a primary variable in pain research and practice is both a scientific and ethical imperative.