Eccentric muscle contraction and stretching evoke mechanical hyperalgesia and modulate CGRP and P2X3 expression in a functionally relevant manner

Dessem, Dean; Ambalavanar, Ranjinidevi; Evancho, Melena; Moutanni, Aicha; Yallampalli, Chandrasekhar; Bai, Guang

doi:10.1016/j.pain.2010.02.022

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Volume 149, Issue 2 , Pages 284-295, May 2010

Eccentric muscle contraction and stretching evoke mechanical hyperalgesia and modulate CGRP and P2X₃ expression in a functionally relevant manner

Dean Dessem
- Department of Neural and Pain Sciences, University of Maryland, 650 West Baltimore Street, Baltimore, MD 21201, USA
- Graduate Program in Neuroscience, University of Maryland, Baltimore, MD, USA
- Corresponding author. Address: Department of Neural and Pain Sciences, University of Maryland, 650 West Baltimore Street, Baltimore, MD 21201, USA. Tel.: +1 410 706 7257; fax: +1 410 706 0193.
Ranjinidevi Ambalavanar
- Department of Neural and Pain Sciences, University of Maryland, 650 West Baltimore Street, Baltimore, MD 21201, USA
Melena Evancho
- Department of Neural and Pain Sciences, University of Maryland, 650 West Baltimore Street, Baltimore, MD 21201, USA
Aicha Moutanni
- Department of Neural and Pain Sciences, University of Maryland, 650 West Baltimore Street, Baltimore, MD 21201, USA
Chandrasekhar Yallampalli
- Department of Obstetrics and Gynecology, University of Texas, Galveston, TX 77555, USA
Guang Bai
- Department of Neural and Pain Sciences, University of Maryland, 650 West Baltimore Street, Baltimore, MD 21201, USA
- Graduate Program in Neuroscience, University of Maryland, Baltimore, MD, USA

Received 16 April 2009; received in revised form 3 January 2010; accepted 12 February 2010. published online 08 March 2010.

Abstract

Non-invasive, movement-based models were used to investigate muscle pain. In rats, the masseter muscle was rapidly stretched or electrically stimulated during forced lengthening to produce eccentric muscle contractions (EC). Both EC and stretching disrupted scattered myofibers and produced intramuscular plasma extravasation. Pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and vascular endothelial growth factor (VEGF) were elevated in the masseter 24h following EC. At 48h, neutrophils increased and ED1 macrophages infiltrated myofibers while ED2 macrophages were abundant at 4d. Mechanical hyperalgesia was evident in the ipsilateral head 4h–4d after a single bout of EC and for 7d following multiple bouts (1 bout/d for 4d). Calcitonin gene-related peptide (CGRP) mRNA increased in the trigeminal ganglion 24h following EC while immunoreactive CGRP decreased. By 2d, CGRP-muscle afferent numbers equaled naive numbers implying that CGRP is released following EC and replenished within 2d. EC elevated P2X₃ mRNA and increased P2X₃ muscle afferent neuron number for 12d while electrical stimulation without muscle contraction altered neither CGRP nor P2X₃ mRNA levels. Muscle stretching produced hyperalgesia for 2d whereas contraction alone produced no hyperalgesia. Stretching increased CGRP mRNA at 24h but not CGRP-muscle afferent number at 2–12d. In contrast, stretching significantly increased the number of P2X₃ muscle afferent neurons for 12d. The sustained, elevated P2X₃ expression evoked by EC and stretching may enhance nociceptor responsiveness to ATP released during subsequent myofiber damage. Movement-based actions such as EC and muscle stretching produce unique tissue responses and modulate neuropeptide and nociceptive receptor expression in a manner particularly relevant to repeated muscle damage.