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

Abstract

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 anti-inflammatory cytokine which 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 anti-inflammatory 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 to 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 that 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, i.e. 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.

Prior voluntary wheel running attenuates neuropathic pain

“…A previous study demonstrated that 8 weeks of voluntary wheel running increases the ratio of gastrocnemius macrophages towards and M2 phenotype. 39 Therefore, we assessed the influence of prior running on macrophage phenotype in the sciatic nerve at 3 and 14 days after CCI. The expression of an M1 marker (iNOS) and an M2 marker (Arg-1) in the injured sciatic nerve were significantly increased at 3 and 14 days after CCI in the locked wheel controls ( P < 0.05; Fig.…”

“…This difference may be attributed to alternative mechanisms between the CCI and intramuscular acidic saline models. For example, chronic pain induced by the latter is dependent on local pro-inflammatory signaling, 39,64 but unlike CCI, it is not dependent on spinal glia. 24,38 This suggests that the long-term protective effects of voluntary wheel running could be mediated by attenuation of central immune signaling.…”

Resident Macrophages in Muscle Contribute to Development of Hyperalgesia in a Mouse Model of Noninflammatory Muscle Pain

“…Immunohistochemistry for macrophages was performed on cryopreserved sections of mouse muscle using rat monoclonal antibody recognizing F4/80 antigen (AbDSerotec, Raleigh, North Carolina), a glycoprotein expressed by mature murine macrophages using techniques we previously published [17;30]. Male and female C57BL/6J mice were anesthetized with an intraperitoneal injection of pentobarbital (50 mg/kg) and transcardially perfused with heparinized saline followed by either 1) 4% paraformaldehyde (clodronate quantification), or 2) PLP fixative (2% paraformaldehyde; 75mM Lysine; 10mM periodate; 0.05M Phosphate Buffer) (Fig.…”

Evaluation of a nanotechnology-based approach to induce gene-expression in human THP-1 macrophages under inflammatory conditions

“…Similarly, M1 macrophages in the spinal cord contribute to chronic pain in rodent model of spinal cord injury (Willemen et al, 2012;Kigerl et al, 2009). Moreover, the induction of an M2 macrophage phenotype reverses or prevents the development of pain and inflammation in rodent models of paw incision and diabetes (Saito et al, 2015), acid-induced muscle pain (Leung et al, 2015), carrageenan-induced inflammation (Willemen et al, 2012) or spinal cord injury (Willemen et al, 2012;Kigerl et al, 2009). In humans (Brueckmann et al, 2004) and mice (Khallou-Laschet et al, 2010), the extended presence of M1 macrophages and a systemic inflammatory response are associated with the development of atherosclerosis and acute coronary syndrome.…”

“…An abnormally prolonged M1 phenotype in macrophages may result in chronic inflammatory processes found in conditions such as chronic pain, atherosclerosis, obesity, etc. Recent studies have shown peripheral (muscle) M1 macrophages are associated in prolonged hyperalgesia in mice (Leung et al, 2015). Similarly, M1 macrophages in the spinal cord contribute to chronic pain in rodent model of spinal cord injury (Willemen et al, 2012;Kigerl et al, 2009).…”