4.6 Article

Regular Aerobic Exercise Attenuates Pain and Anxiety in Mice by Restoring Serotonin-Modulated Synaptic Plasticity in the Anterior Cingulate Cortex

Journal

MEDICINE & SCIENCE IN SPORTS & EXERCISE
Volume 54, Issue 4, Pages 566-581

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1249/MSS.0000000000002841

Keywords

PAIN; ANXIETY; AEROBIC EXERCISE; SEROTONIN; 5-HT1A; 5-HT7

Categories

Funding

  1. National Nature Science Foundation of China [81671081, 81772462]

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Our study investigated the effects of regular aerobic exercise on pain and anxiety behaviors and the underlying neural mechanisms. We found that regular aerobic exercise increased serotonin release and modulated synaptic plasticity in the ACC. The modulation effects were mediated by 5-HT1A and 5-HT7 receptors. These findings suggest that regular aerobic exercise can improve pain and concomitant anxiety behaviors through serotonin-mediated mechanisms in the ACC.
Purpose Clinical studies found that regular aerobic exercise has analgesic and antianxiety effects; however, the underlying neural mechanisms remain unclear. Multiple studies have suggested that regular aerobic exercise may exert brain-protective effects by promoting the release of serotonin, which may be a pain modulator. Anterior cingulate cortex (ACC) is a key brain area for pain information processing, receiving dense serotonergic innervation. As a result, we hypothesized that exercise may increase the release of serotonin in the ACC, thus improving pain and anxiety behaviors. Methods Integrative methods were used, including behavioral, electrophysiological, pharmacological, biochemical, and genetic approaches, to explore the effects of regular aerobic exercise and the underlying neural mechanisms. Results Regular aerobic exercise in the form of voluntary wheel running for 30 min daily for 15 d showed significant effectiveness in relieving pain and concomitant anxiety in complete Freund's adjuvant-induced chronic inflammation pain models. c-Fos staining and multielectrode array recordings revealed alterations in neuronal activities and synaptic plasticity in the ACC. Moreover, systemic pharmacological treatment with 4-chloro-dl-phenylalanine (PCPA) to deplete endogenous serotonin and local delivery of serotonin to the ACC revealed that exercise-related serotonin release in the ACC bidirectionally modulates pain sensitization and anxiety behaviors by modulating synaptic plasticity in the ACC. Furthermore, we found that 5-HT1A and 5-HT7 receptors mediated the serotonin modulation effects under conditions of regular aerobic exercise through local infusion of a selective antagonist and shRNA in the ACC. Conclusions Our results reveal that regular aerobic exercise can increase serotonin release and modulate synaptic plasticity in the ACC, ultimately improving pain and concomitant anxiety behaviors through the functions of the 5-HT1A and 5-HT7 receptors.

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