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

Abstract

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.

Intraarticular induction of interleukin‐1β expression in the adult mouse, with resultant temporomandibular joint pathologic changes, dysfunction, and pain

“…Our data demonstrate a decrease in the resistance to jaw opening in the activated Col1-IL-1␤ XAT mice (transgene plus Cre) as compared with the controls (transgene plus gfp and transgene plus saline), which suggests pain avoidance ( Figure 6). This supports the pain-adaptation hypothesis and other pain models in which force is decreased (35,36,39).…”

The pharmacological properties and clinical use of valdecoxib, a new cyclo‐oxygenase‐2‐selective inhibitor

“…12 Furthermore, in the Hargreaves hyperalgesia model, valdecoxib was able to reverse hyperalgesia by 97%, compared with 74% for naproxen. 13 In the rat adjuvant-induced arthritis model of chronic inflammation, the anti-inflammatory effect of valdecoxib was similar to that of indometacin, with maximal reductions in the swelling of the hind limb of 95% for the former and 93% for the latter. 14 Valdecoxib, at doses of 3, 10, 30 and 100 mg ⁄ kg, was also effective in reversing hyperalgesia and allodynia in a Brennan model of post-operative pain, in which nociception was produced by surgical incisions.…”

Neurotrophin-3 Reverses Chronic Mechanical Hyperalgesia Induced by Intramuscular Acid Injection

“…Recently, animal models have been developed to simulate muscle-derived chronic pain (Kehl et al, 2000;Sluka et al, 2001;Radhakrishnan et al, 2003;Schafers et al, 2003). One in particular uses acid injection into the gastrocnemius to produce a persistent mechanical, but not thermal, hyperalgesia of the hindpaw ).…”