ASIC3 Is Required for Development of Fatigue-Induced Hyperalgesia

Nicholas S Gregory; Renan G Brito; Maria Cláudia G Oliveira Fusaro; Kathleen A Sluka

doi:10.1007/s12035-014-9055-4

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ASIC3 Is Required for Development of Fatigue-Induced Hyperalgesia

Journal article

Peer reviewed

ASIC3 Is Required for Development of Fatigue-Induced Hyperalgesia

Nicholas S Gregory, Renan G Brito, Maria Cláudia G Oliveira Fusaro and Kathleen A Sluka

Molecular neurobiology, Vol.53(2), pp.1020-1030

03/2016

DOI: 10.1007/s12035-014-9055-4

PMCID: PMC4499332

PMID: 25577172

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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.

Electric Stimulation

Hyperalgesia - metabolism

Sodium Chloride - pharmacology

Mice, Inbred C57BL

Male

Muscle, Skeletal - innervation

Down-Regulation - drug effects

Pain - pathology

Gene Knockdown Techniques

Hyperalgesia - physiopathology

Macrophages - metabolism

Animals

Muscle Contraction - drug effects

Pain - physiopathology

Gene Deletion

Muscle Fatigue - drug effects

Muscle, Skeletal - drug effects

Hyperalgesia - etiology

Pain - etiology

Female

Macrophages - drug effects

Acid Sensing Ion Channels - metabolism

Hydrogen-Ion Concentration

Details

Title: Subtitle: ASIC3 Is Required for Development of Fatigue-Induced Hyperalgesia
Creators: Nicholas S Gregory - Neuroscience Graduate Program, Pain Research Program, Department of Physical Therapy and Rehabilitation Science, University of Iowa, 1-248 MEB, Iowa City, IA, 52242, USA
Renan G Brito - Department of Physiology, Federal University of Sergipe, Aracaju, Brazil
Maria Cláudia G Oliveira Fusaro - Faculdade de Ciências Aplicadas, State University of Campinas-UNICAMP, Campinas, Brazil
Kathleen A Sluka - Neuroscience Graduate Program, Pain Research Program, Department of Physical Therapy and Rehabilitation Science, University of Iowa, 1-248 MEB, Iowa City, IA, 52242, USA. kathleen-sluka@uiowa.edu
Resource Type: Journal article
Publication Details: Molecular neurobiology, Vol.53(2), pp.1020-1030
DOI: 10.1007/s12035-014-9055-4
PMID: 25577172
PMCID: PMC4499332
NLM abbreviation: Mol Neurobiol
ISSN: 0893-7648
eISSN: 1559-1182
Publisher: United States
Grant note: AR053509 / NIAMS NIH HHS R01 AR052316 / NIAMS NIH HHS T32 NS045549 / NINDS NIH HHS AR061371 / NIAMS NIH HHS T32 GM007337 / NIGMS NIH HHS R01 AR061371 / NIAMS NIH HHS R01 AR053509 / NIAMS NIH HHS
Language: English
Date published: 03/2016
Academic Unit: Iowa Neuroscience Institute; Nursing; Physical Therapy and Rehabilitation Science; Neuroscience and Pharmacology
Record Identifier: 9984040259002771

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