Neuroplastic mechanisms of chronic pain: Implications and future directions

Abstract

Chronic pain is now increasingly viewed as aberrant neuroplasticity rather than a protracted expression of peripheral nociception. This review integrates current knowledge through the lens of a peripheral-to-central paradigm, whereby peripheral sensory sensitization contributes to pain initiation, spinal excitation–inhibition imbalance and glianeuron signaling amplify and sustain central sensitization, and supraspinal corticolimbic and reward-network remodeling contributes to persistent pain as well as affective or cognitive comorbidities. Across neuropathic, inflammatory, osteoarthritis-related, pelvic, postoperative, visceral, and diabetic pain, higher-level processes show broad cross-disorder convergence, whereas the dominant molecular mediators, immune-cell populations, and circuit mechanisms frequently remain disease- and model-specific. The strongest mechanistic evidence comes from animal studies, while neuroimaging, behavioral phenotyping, and molecular markers are complementary but not yet clinically validated measures of pain-related plasticity. Pharmacological and non-pharmacological interventions have shown preclinical potential for modulating these mechanisms, although evidence for mechanism-guided precision treatment remains limited. Future studies need to implement longitudinal, sex-inclusive, and cross-model designs that integrate cell-specific manipulation, multimodal imaging, multi-omics, and prospective clinical validation in order to differentiate causal drivers from secondary adaptations and translate knowledge of neuroplastic mechanisms into clinically actionable strategies.