Exercise therapy for chronic pain: an updated perspective on mesocorticolimbic system function

Patients with chronic pain often experience behavioral issues linked to pain, depression, and other emotional disorders. These problems stem from dysfunction in the mesocorticolimbic system, and exercise offers a safe, accessible, and effective alternative. It not only reduces pain but also activates multiple neural pathways, helping restore normal function. First, in the periphery, exercise promotes the release of myokines, which are essential for the body-brain connection and influence neural activity. IGF-1, released from muscles during exercise, can cross the blood-brain barrier and affect the brain. IGF-1 specifically targets orexin neurons in the hypothalamus, which then stimulate dopamine neurons in the ventral tegmental area, triggering the reward system. Second, exercise can reshape neural circuits and restore mesocorticolimbic function, reducing chronic pain and related issues. We showed that exercise activates neurons in the basal nucleus of the amygdala that project to the nucleus accumbens, supporting patients' goal-directed behavior. Moreover, inhibiting GABAergic neurons in the central nucleus of the amygdala decreases freezing behavior. Third, chronic pain often leads to depression, mainly due to reduced activity of serotonin (5-HT) neurons in the dorsal raphe nucleus, which impairs the brain's reward system. Exercise boosts activity of 5-HT neurons in the dorsal raphe nucleus. Furthermore, exercise can modify gene expression through epigenetic mechanisms, leading to long-lasting improvements in brain function and behavior. Overall, exercise can restore brain function, helping individuals overcome chronic pain and lead healthier lives. These findings support exercise therapy as a key component of chronic pain management and suggest mesocorticolimbic mechanisms underlying its effects.