Development and pharmacological characterization of a rat model of osteoarthritis pain

Purdue Pharma L.P., Stamford, Connecticut, United States
Pain (Impact Factor: 5.84). 05/2005; 114(3):339-46. DOI: 10.1016/j.pain.2004.11.008
Source: PubMed

ABSTRACT Osteoarthritis (OA) is an age-related joint disease characterized by degeneration of articular cartilage and is associated with chronic pain. Although several experimental models of OA have been employed to investigate the underlying etiologies of the disease, there has been relatively little investigation into development of animal models of OA to study the pain associated with the condition. In the present study, we investigated OA induced by injection of either iodoacetate or papain into the knee joint of rats, and assessed the joint degeneration with radiographic analyses and measured pain behavior using hind limb weight bearing. We found that injection of iodoacetate, but not papain, resulted in a chronic joint degeneration as measured by decreased bone mineral content and bone mineral density, necrosis of articular cartilage and osteophyte formation. These pathological changes were associated with pain that manifested as time- and concentration-dependent alterations in hind limb weight bearing. These alterations in hind limb weight bearing were reversed with morphine, but were not significantly affected by acute administration of either indomethacin or celecoxib. However, administration of 30 mg/kg celecoxib twice daily for 10 days resulted in a significant restoration of hind limb weight bearing. We conclude that the iodoacetate model of OA is a relevant animal model to study pain associated with OA, and can be used to test potential therapeutic agents.


Available from: James D Pomonis, Sep 17, 2014
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    ABSTRACT: The pharmacological inhibition of anandamide (AEA) hydrolysis by fatty acid amide hydrolase (FAAH) attenuates pain in animal models of osteoarthritis but has failed in clinical trials. This may have occurred because AEA also activates transient receptor potential vanilloid type-1 (TRPV1), which contributes to pain development. Therefore, we investigated the effectiveness of the dual FAAH-TRPV1 blocker OMDM-198 in an MIA-model of osteoarthritic pain. We first investigated the MIA-induced model of osteoarthritis by 1) characterizing the pain phenotype and degenerative changes within the joint using X-ray microtomography and 2) evaluating nerve injury and inflammation marker (ATF-3 and IL-6) expression in the lumbar DRG of osteoarthritic rats and differences in gene and protein expression of the cannabinoid CB1 receptors FAAH and TRPV1. Furthermore, we compared OMDM-198 with compounds acting exclusively on FAAH or TRPV1. Osteoarthritis was accompanied by the fragmentation of bone microstructure and destroyed cartilage. An increase of the mRNA levels of ATF3 and IL-6 and an upregulation of AEA receptors and FAAH in the DRG was observed. OMDM-198 showed anti-hyperalgesic effects in the osteoarthritis model, which were comparable to those of a selective TRPV1 antagonist, SB-366,791, and a selective FAAH inhibitor, URB-597. The effect of OMDM-198 was attenuated by the CB1 receptor antagonist, AM-251, and by the non-pungent TRPV1 agonist, olvanil, suggesting its action as an "indirect" CB1 agonist and TRPV1 antagonist. These results suggest an innovative strategy for the treatment of osteoarthritis, which may yield more satisfactory results than those obtained so far with selective FAAH inhibitors in human osteoarthritis.
    Pain 02/2015; 156(5). DOI:10.1097/j.pain.0000000000000132 · 5.84 Impact Factor
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