A new animal model for assessing mechanisms and management of muscle hyperalgesia

Musculoskeletal pain is one of the most frequent symptoms for which medical assistance is sought. Yet, the majority of our knowledge regarding pain physiology is based on studies of cutaneous tissue. Comparatively little is known about activation of visceral, joint and perhaps least of all, musculoskeletal nociceptors although clinically-treated pain originates principally in these structures. Studies elucidating the mechanisms of muscle hyperalgesia have been hampered by the lack of an animal model that permits the evaluation of hypotheses using behavioral, biochemical, pharmacological, anatomical and molecular experimental approaches. Here we describe an animal model of muscle hyperalgesia we recently developed that permits such multidisciplinary investigation. This model employs the intramuscular injection of carrageenan, a chemical stimulus which evokes a well recognized model of cutaneous inflammation and is reported to activate muscle nociceptors. Intramuscular carrageenan evokes a time- and dose-dependent reduction in forelimb grip force that is anatomically specific. The carrageenan-evoked reduction in grip force is blocked by the mu-opioid agonist levorphanol in a dose-dependent, stereoselective and naltrexone-reversible manner. This behavioral dependent measure is also significantly reversed by agents used clinically to treat muscle pain, indomethacin and dexamethasone, as well as the non-competitive N-methyl-D-aspartate receptor antagonist MK801. Finally, evidence that reduction in grip force is in part mediated by small, unmyelinated afferents is provided by the demonstration that neonatal capsaicin treatment significantly reduced carrageenan-evoked behavioral hyperalgesia ( approximately 45% reduction) and reduced muscle content of immunoreactive CGRP ( approximately 60% reduction) relative to control levels. Collectively, these findings provide converging lines of evidence for the validity of this animal model to investigate mechanisms involved in the development of muscle hyperalgesia.