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ASIC3 Is Required for Development of Fatigue-Induced Hyperalgesia

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Abstract

An acute bout of exercise can exacerbate pain, hindering participation in regular exercise and daily activities. The mechanisms underlying pain in response to acute exercise are poorly understood. We hypothesized that proton accumulation during muscle fatigue activates acid-sensing ion channel 3 (ASIC3) on muscle nociceptors to produce hyperalgesia. We investigated the role of ASIC3 using genetic and pharmacological approaches in a model of fatigue-enhanced hyperalgesia. This model uses two injections of pH 5.0 saline into muscle in combination with an electrically induced fatigue of the same muscle just prior to the second injection of acid to induce mechanical hyperalgesia. We show a significant decrease in muscle force and decrease in muscle pH after 6 min of electrical stimulation. Genetic deletion of ASIC3 using knockout mice and pharmacological blockade of ASIC3 with APETx2 in muscle prevents the fatigue-enhanced hyperalgesia. However, ASIC3−/− mice and APETx2 have no effect on the fatigue response. Genetic deletion of ASIC3 in primary afferents innervating muscle using an HSV-1 expressing microRNA (miRNA) to ASIC3 surprisingly had no effect on the development of the hyperalgesia. Muscle fatigue increased the number of macrophages in muscle, and removal of macrophages from muscle with clodronate liposomes prevented the development of fatigue-enhanced hyperalgesia. Thus, these data suggest that fatigue reduces pH in muscle that subsequently activates ASIC3 on macrophages to enhance hyperalgesia to muscle insult.

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Acknowledgments

Funded by the National Institute of Health grants AR061371 and AR053509. The authors wish to thank Dr. Roxanne Walder for advice on qPCR and Lynn Rasmussen and Jing Danielson for technical assistance.

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The authors declare no competing financial interests.

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Authors and Affiliations

  1. Neuroscience Graduate Program, Pain Research Program, Department of Physical Therapy and Rehabilitation Science, University of Iowa, 1-248 MEB, Iowa City, IA, 52242, USA

    Nicholas S. Gregory & Kathleen A. Sluka

  2. Department of Physiology, Federal University of Sergipe, Aracaju, Brazil

    Renan G. Brito

  3. Faculdade de Ciências Aplicadas, State University of Campinas-UNICAMP, Campinas, Brazil

    Maria Cláudia G. Oliveira Fusaro

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  1. Nicholas S. Gregory
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Correspondence to Kathleen A. Sluka.

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Gregory, N.S., Brito, R.G., Fusaro, M.C.G.O. et al. ASIC3 Is Required for Development of Fatigue-Induced Hyperalgesia. Mol Neurobiol 53, 1020–1030 (2016). https://doi.org/10.1007/s12035-014-9055-4

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