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

  • Wei-Yi Gong
    Affiliations
    Department of Pain Management, Xuanwu Hospital, Capital Medical University, Beijing, China

    Department of Physical Therapy and Rehabilitation Science, University of Iowa, Carver College of Medicine, Iowa City, Iowa
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  • Ramy E. Abdelhamid
    Affiliations
    Department of Physical Therapy and Rehabilitation Science, University of Iowa, Carver College of Medicine, Iowa City, Iowa
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  • Carolina S. Carvalho
    Affiliations
    Department of Physical Therapy and Rehabilitation Science, University of Iowa, Carver College of Medicine, Iowa City, Iowa
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  • Kathleen A. Sluka
    Correspondence
    Address reprint requests to Kathleen A. Sluka, PhD, PT, Department of Physical Therapy and Rehabilitation Science, University of Iowa, Carver College of Medicine, 500 Newton Road, 1-248 Medical Education Building, Iowa City, IA 52242.
    Affiliations
    Department of Physical Therapy and Rehabilitation Science, University of Iowa, Carver College of Medicine, Iowa City, Iowa
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      Highlights

      • Removal of macrophages from muscle prevents development of chronic muscle hyperalgesia induced by repeated acid injections.
      • Blockade of toll-like receptor 4 (TLR4) or activation prevents development of chronic muscle pain.
      • Replacement of 1 acid injection with either lipopolysaccharide or interleukin-6 to mimic macrophage activation results in development of hyperalgesia.
      • Acid, lipopolysaccharide, and interleukin-6 increase the number of macrophages in muscle and induce release of cytokines from cultured macrophages.
      • Thus, macrophages play a critical role in the development of chronic 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. In this study we investigate the role of resident macrophages in the noninflammatory muscle pain model induced by 2 pH 4.0 preservative-free sterile saline (pH 4.0) injections 5 days apart in the gastrocnemius muscle. We showed 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 before 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 toll-like receptor 4 (TLR4) 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, or the inflammatory cytokine interleukin (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 showed that resident macrophages in muscle are key to development of chronic muscle pain.

      Perspective

      This article presents evidence for the role of macrophages in the development of chronic muscle pain using a mouse model. These data suggest that macrophages could be a potential therapeutic target to prevent transition of acute to chronic muscle pain particularly in tissue acidosis conditions.

      Key words

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