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Regular physical activity prevents chronic pain by altering resident muscle macrophage phenotype and increasing interleukin-10 in mice

Leung, Audreya; Gregory, Nicholas S.a,b; Allen, Lee-Ann H.a,c; Sluka, Kathleen A.a,b,d,*

doi: 10.1097/j.pain.0000000000000312
Research Paper
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Regular physical activity in healthy individuals prevents development of chronic musculoskeletal pain; however, the mechanisms underlying this exercise-induced analgesia are not well understood. Interleukin-10 (IL-10), an antiinflammatory cytokine that can reduce nociceptor sensitization, increases during regular physical activity. Since macrophages play a major role in cytokine production and are present in muscle tissue, we propose that physical activity alters macrophage phenotype to increase IL-10 and prevent chronic pain. Physical activity was induced by allowing C57BL/6J mice free access to running wheels for 8 weeks and compared to sedentary mice with no running wheels. Using immunohistochemical staining of the gastrocnemius muscle to label regulatory (M2, secretes antiinflammatory cytokines) and classical (M1, secretes proinflammatory cytokines) macrophages, the percentage of M2-macrophages increased significantly in physically active mice (68.5% ± 4.6% of total) compared with sedentary mice (45.8% ± 7.1% of total). Repeated acid injections into the muscle enhanced mechanical sensitivity of the muscle and paw in sedentary animals, which does not occur in physically active mice; no sex differences occur in either sedentary or physically active mice. Blockade of IL-10 systemically or locally prevented the analgesia in physically active mice, ie, mice developed hyperalgesia. Conversely, sedentary mice pretreated systemically or locally with IL-10 had reduced hyperalgesia after repeated acid injections. Thus, these results suggest that regular physical activity increases the percentage of regulatory macrophages in muscle and that IL-10 is an essential mediator in the analgesia produced by regular physical activity.

Regular physical activity increases the percentage of M2 macrophages and prevents the development of chronic muscle hyperalgesia through activation of muscle interleukin-10 receptors.

aUniversity of Iowa Carver College of Medicine, Iowa City, IA, USA

bNeuroscience Graduate Program, University of Iowa, Iowa City, IA, USA

Departments of cInternal Medicine and

dPhysical Therapy and Rehabilitation Science, University of Iowa Carver College of Medicine, Iowa City, IA, USA

Corresponding author. Address: Department of Physical Therapy and Rehabilitation Science, University of Iowa, 1-248 MEB, 500 Newton Rd, Iowa City, IA 52242, USA. Tel.: (319) 335-9791; fax: (319) 335-9707. E-mail address: kathleen-sluka@uiowa.edu (K. A. Sluka).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received May 29, 2015

Accepted July 24, 2015

© 2016 International Association for the Study of Pain
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