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

Abstract

Macrophages play a role in innate immunity within the body, are located in muscle tissue, and can release inflammatory cytokines that sensitize local nociceptors. Here we investigate the role of resident macrophages in the non-inflammatory muscle pain model induced by 2 pH 4.0 injections 5 days apart in the gastrocnemius muscle. We demonstrate that injecting 2 pH 4.0 injections into the gastrocnemius muscle increased the number of local muscle macrophages, and depleting muscle macrophages with clodronate liposomes prior to acid injections attenuated the hyperalgesia produced by this model. To further examine the contribution of local macrophages to this hyperalgesia, we injected mice intramuscularly with C34, a TLR4 receptor antagonist. When given before the first pH 4.0 injection, C34 attenuated the muscle and tactile hyperalgesia produced by the model. However, when given before the second injection C34 had no effect on the development of hyperalgesia. Then to test whether activation of local macrophages sensitizes nociceptors to normally non-nociceptive stimuli we replaced either the first or second acid injection with the immune cell activator lipopolysaccharide (LPS), or the inflammatory cytokine interleukin-6 (IL-6). Injecting LPS or IL-6 instead of the either the first or second pH 4.0 injection resulted in a dose-dependent increase in paw withdrawal responses and decrease in muscle withdrawal thresholds. The highest doses of LPS and IL-6 resulted in development of hyperalgesia bilaterally. The present study shows that resident macrophages in muscle are key to development of chronic muscle pain.

Thin‐fibre receptors expressing acid‐sensing ion channel 3 contribute to muscular mechanical hypersensitivity after exercise

“…Involvement of ASIC3 in muscular mechanical hypersensitivity was initially established in a non‐inflammatory muscle pain model induced by acidic saline injections (Sluka et al, ). This model later found that ASIC3 in the resident macrophages were responsible (Gong, Abdelhamid, Carvalho, & Sluka, ). In the current DOMS model, the possibility of macrophage ASIC3 involvement was low if not zero, as accumulating mononuclear cells, including macrophages, were rarely observed in the entire cross sectional area of the LC muscle (Hayashi et al, ).…”

Mechanisms underlying immobilization‐induced muscle pain in rats

“…The number of macrophages, particularly M1 macrophages, and IL‐1β mRNA expression both increased in immobilized muscle. Macrophages could contribute to the development of noninflammatory muscle pain in a mouse model and accumulate in skeletal muscle during cast immobilization . They are mainly classified into M1 and M2 phenotypes.…”

“…Macrophages also contribute to noninflammatory muscle pain development in mouse models . They accumulate in the immobilized skeletal muscles and release inflammatory cytokines, such as tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), and IL‐6 .…”

Macrophage polarization contributes to local inflammation and structural change in the multifidus muscle after intervertebral disc injury

“…After muscle injury, macrophages regulate inflammation, tissue integrity and pain [22,6,23]. M1 (proinflammatory) and M2 (anti-inflammatory) macrophage subtypes contribute at different times during healing.…”