Pain Chronicity and Relief: From Molecular Basis to Exercise-Based Rehabilitation

Chronic pain is a significant and complex health condition characterized by persistent or recurrent pain lasting more than three months. Exercise-based rehabilitation is an effective non-pharmacological intervention, yet its underlying mechanisms have not been fully elucidated. This review systematically maps the molecular pathways of exercise-induced analgesia onto the pathophysiological cascades of chronic pain, aiming to fill a key gap in the current literature. It explores the molecular and cellular mechanisms underpinning the pathophysiology of chronic pain, indicating that the persistence of chronic pain stems from peripheral sensitization driven by inflammatory mediators and central sensitization involving glial cell activation and N-methyl-D-aspartate (NMDA) receptor-mediated neuroplasticity. Exercise can interrupt these pathological cascades through multi-system adaptations, including activation of the endogenous opioid and serotonergic systems activation and anti-inflammation. However, a significant gap remains in translating this mechanistic understanding of chronic pain into optimized, personalized exercise prescriptions, requiring future research into different exercise modalities, sex-specific responses, and the impact of comorbidities.