Journal article
P2X4 Receptors on Muscle Macrophages Are Required for Development of Hyperalgesia in an Animal Model of Activity-Induced Muscle Pain
Molecular neurobiology, Vol.57(4), pp.1917-1929
04/2020
DOI: 10.1007/s12035-019-01852-x
PMCID: PMC7124976
PMID: 31898158
Abstract
Activity-induced pain is common in those with chronic musculoskeletal pain and limits participation in daily activities and exercise. Our laboratory developed a model of activity-induced pain and shows that depletion of muscle macrophages prevents development of hyperalgesia. Adenosine triphosphate (ATP) is released from fatiguing muscle and activates purinergic receptors (P2X), and P2X4 receptors are expressed on macrophages. We hypothesized that exercise releases ATP to activate P2X4 receptors on muscle macrophages, which subsequently release interleukin-1β (IL-1β) to produce hyperalgesia. In an animal model of activity-induced pain, using male and female C57BL6/J mice, we show increased expression of P2X4 on muscle macrophages, and blockade of P2X4 receptors in muscle prevented development of hyperalgesia. Using a lentivirus expressing an artificial micro-RNA to P2X4 under the control of a CD68 promoter, we decreased expression of P2X4 mRNA in cultured macrophages, decreased expression of P2X4 protein in muscle macrophages in vivo, and prevented development of activity-induced hyperalgesia. We further show that macrophages primed with LPS differentially released IL-1β when treated with ATP in neutral or acidic pH. Lastly, blockade of IL-1β in muscle prevented development of hyperalgesia in this model. Thus, our data suggest that P2X4 receptors could be a valid pharmacological target to control activity-induced muscle pain experienced by patients with chronic musculoskeletal pain.
Details
- Title: Subtitle
- P2X4 Receptors on Muscle Macrophages Are Required for Development of Hyperalgesia in an Animal Model of Activity-Induced Muscle Pain
- Creators
- Maria Claudia Oliveira-Fusaro - School of Applied Sciences, State University of Campinas-UNICAMP, Limeira, 13484-350, BrazilNicholas S Gregory - Neuroscience Graduate Program, Pain Research Program, Department of Physical Therapy and Rehabilitation Science, The University of Iowa, Iowa City, IA, 52242, USASandra J Kolker - Neuroscience Graduate Program, Pain Research Program, Department of Physical Therapy and Rehabilitation Science, The University of Iowa, Iowa City, IA, 52242, USALynn Rasmussen - Neuroscience Graduate Program, Pain Research Program, Department of Physical Therapy and Rehabilitation Science, The University of Iowa, Iowa City, IA, 52242, USALee-Ann H Allen - Departments of Internal Medicine and Microbiology and Immunology, The University of Iowa, Iowa City, IA, 52242, USAKathleen A Sluka - Neuroscience Graduate Program, Pain Research Program, Department of Physical Therapy and Rehabilitation Science, The University of Iowa, Iowa City, IA, 52242, USA. kathleen-sluka@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Molecular neurobiology, Vol.57(4), pp.1917-1929
- DOI
- 10.1007/s12035-019-01852-x
- PMID
- 31898158
- PMCID
- PMC7124976
- NLM abbreviation
- Mol Neurobiol
- ISSN
- 0893-7648
- eISSN
- 1559-1182
- Publisher
- United States
- Grant note
- Finance Code 001 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) R01 AR061371 / NIAMS NIH HHS AR061371 / National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) R01 AR073187 / NIAMS NIH HHS N/A / The University of Iowa Carver College of Medicine 2014/01119-4 / Sao Paulo Research Foundation (FAPESP)
- Language
- English
- Date published
- 04/2020
- Academic Unit
- Microbiology and Immunology; Infectious Diseases; Iowa Neuroscience Institute; Nursing; Anesthesia; Physical Therapy and Rehabilitation Science; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984070633302771
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