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Molecular Neurobiology

, Volume 53, Issue 2, pp 1020–1030 | Cite as

ASIC3 Is Required for Development of Fatigue-Induced Hyperalgesia

  • Nicholas S. Gregory
  • Renan G. Brito
  • Maria Cláudia G. Oliveira Fusaro
  • Kathleen A. Sluka
Article

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.

Keywords

Pain Exercise Proton Acid ASIC Hyperalgesia Macrophage 

Notes

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.

Conflict of Interest

The authors declare no competing financial interests.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Nicholas S. Gregory
    • 1
  • Renan G. Brito
    • 2
  • Maria Cláudia G. Oliveira Fusaro
    • 3
  • Kathleen A. Sluka
    • 1
  1. 1.Neuroscience Graduate Program, Pain Research Program, Department of Physical Therapy and Rehabilitation ScienceUniversity of IowaIowa CityUSA
  2. 2.Department of PhysiologyFederal University of SergipeAracajuBrazil
  3. 3.Faculdade de Ciências AplicadasState University of Campinas-UNICAMPCampinasBrazil

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