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

Abstract

PurposeClinical 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.MethodsIntegrative methods were used, including behavioral, electrophysiological, pharmacological, biochemical, and genetic approaches, to explore the effects of regular aerobic exercise and the underlying neural mechanisms.ResultsRegular 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.ConclusionsOur 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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“…We first compared 5-HT levels between animals in the control group and the PCPA group to examine the depletion effect on blood 5-HT under PCPA [300 mg/kg, intraperitoneal injection (i.p.)]. The comparison depicted significant differences ( Figure 1A ), consistent with the previous studies ( Farabollini et al, 1988 ; Zhou et al, 2022b ).…”

Multi-Region Microdialysis Imaging Platform Revealed Dorsal Raphe Nucleus Calcium Signaling and Serotonin Dynamics during Nociceptive Pain

“…In addition, extensive studies from humans and rodents have shown the fundamental roles of the ACC in acute and chronic pain [ 71 ]. For instance, serotonin in the ACC contributes to relieving pain and anxiety through synaptic plasticity triggered by regular aerobic exercise [ 72 ].…”

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“…Recently, a new study described that regular aerobic exercise had significant effects in relieving pain and concomitant anxiety in the chronic inflammatory pain model. Regular aerobic exercise could increase 5-HT release and attenuate pain-induced LTP occlusion in the ACC through the 5-HT 1A and 5-HT 7 receptors ( Zhou et al, 2022 ). Therefore, 5-HT may be modulating injury-related anxiety by directly or indirectly changing the pre-LTP of excitatory transmission in the ACC.…”