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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Prostacyclin Antagonism Reduces Pain and Inflammation in Rodent Models of Hyperalgesia and Chronic Arthritis

Merck Frosst Centre for Therapeutic Research, Kirkland, Québec, Canada

The inhibition of prostaglandin (PG) synthesis is at the center of current anti-inflammatory therapies. Because cyclooxygenase-2 (COX-2) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of multiple PGs, there is currently a strong focus on characterizing the role of the different PGs in the inflammation process and development of arthritis. Evidence to date suggests that both PGE₂ and PGI₂ act as mediators of pain and inflammation. Most of the data indicating a role for PGI₂ in this context have been generated in animal models of acute pain. Herein, we describe the role of PGI₂ in models of osteoarthritis (OA) and rheumatoid arthritis using a highly selective PGI₂ receptor (IP, Ptgir) antagonist and IP receptor-deficient mice. In the rat OA model using monoiodoacetate injection into the knee joint, the IP antagonist reduced pain with an efficacy approaching that of the NSAID diclofenac. In a chronic model of inflammatory arthritis, collagen-antibody induced arthritis model in mice, IP receptor-deficient mice displayed a 91% reduction in arthritis score. Interestingly, pretreatment with the IP [N-[4-(imidazolidin-2-ylideneamino)-benzyl]-4-methoxy-benzamide] antagonist in this model also caused a significant reduction of the symptoms, whereas administration of the compound after the initiation of arthritis had no detectable effect. Our data indicate that, in addition to its role in acute inflammation, PGI₂ is involved in the development of chronic inflammation. The results also suggest that the inhibition of PGI₂ synthesis by NSAIDs and COX-2 inhibitors, in addition to that of PGE₂, contributes to their efficacy in treating the signs of arthritis.

Address correspondence to: Dr. Laurent P. Audoly, One MedImmune Way, Gaithersburg, MD 20878. E-mail: audolyl{at}medimmune.com

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