N-methyl-d-aspartate receptor subunits interacting with regulators mediate neuropathic pain: from mechanisms to therapy.

NMDARs and their interacting proteins drive central sensitization in neuropathic pain, yet their pathological effects are critically shaped by upstream neuroendocrine regulators. This review synthesizes evidence across three dimensions: (i) glucocorticoids amplify pain via spinal glucocorticoid receptor signaling, and prior stress history reprograms HPA axis reactivity, thereby determining individual pain susceptibility; (ii) sex hormones produce divergent effects: estrogen exacerbates while progesterone protects and pain mechanisms are sexually dimorphic, with males and females engaging distinct immune and neuronal pathways; (iii) current therapies (ketamine, gabapentinoids) have significant limitations. Emerging preclinical strategies include neuroendocrine-directed interventions (glucocorticoid receptor antagonists, progesterone, sex-stratified trial designs) alongside protein-protein interaction disruptors targeting α2δ-1, Panx1, or PSD-95. Collectively, targeting upstream hormonal drivers offers a paradigm shift from broad NMDAR blockade toward more selective and tolerable treatments, though rigorous validation across sexes and pain phases remains essential.