Exercise-Induced Hypoalgesia: Cellular and Molecular Mechanisms Linking Pain Modulation and Stress Regulation—A Narrative Review

Exercise-induced hypoalgesia (EIH) illustrates how physical activity can reshape the biology of pain while simultaneously influencing the systems that regulate stress. Acute and repeated exercise can reduce pain sensitivity in healthy individuals and in some chronic pain populations, yet the magnitude and consistency of these effects vary substantially across individuals, diagnoses, and exercise protocols. This variability suggests that EIH is not a uniform response, but an adaptive multisystem process shaped by neural, immune, endocrine, metabolic, musculoskeletal, and psychosocial factors. This narrative review synthesizes evidence linking pain modulation and stress regulation across biological scales. Exercise engages descending pain modulatory circuits involving the periaqueductal gray, rostral ventromedial medulla, and spinal dorsal horn, while also influencing endogenous opioid, endocannabinoid, serotonergic, and noradrenergic signaling. These pathways are relevant not only to nociceptive inhibition, but also to affective regulation, hypothalamic–pituitary–adrenal axis activity, autonomic balance, and perceived stress. In parallel, exercise-related neuroimmune changes, including modulation of microglial activity, cytokine signaling, and myokine release from skeletal muscle, may connect peripheral metabolic activity with central mechanisms of pain and stress adaptation. Importantly, the evidence supporting these mechanisms differs in strength: some findings derive from human experimental and clinical studies, whereas others are supported mainly by preclinical or translational research. By distinguishing direct evidence from mechanistic inference, this review highlights how exercise may support hypoalgesia, stress resilience, and functional recovery, while also emphasizing the need for biomarker-informed, personalized exercise strategies in chronic pain management.