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

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Abstract
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.