Role of COX-1-and COX-2-synthesized prostaglandins in a rat model of arthritic pain

An appropriate animal model for investigation of antiinflammatory analgesic effects of NSAIDs is the pain-induced functional impairment model in the r at (PIFIR model). The PIFIR model provides a model of inflammatory and chro nic pain similar to that of clinical gout. We investigated the possible rol e of peripheral prostaglandins synthesized by COX-1 and COX-2 in arthritic pain produced by uric acid in the rat PIFIR model. For this purpose, the an tinociceptive effects of indomethacin, a nonselective COX-1/COX-2 inhibitor , and those of SC-560 and MK-966 (Vioxx), selective inhibitors of COX-1 and COX-2, respectively, on the functional impairment induced by intraarticula r (i.a.) injection of uric acid into the knee joint of the right hindlimb w ere compared. The antinociceptive efficacy was determined from the area und er the curve (AUC) values obtained from the time course of the antinocicept ive effect. Animals received vehicle, 100 mug indomethacin, 100 mug SC-560, or 50 mug of MK-966 (these drug doses were selected from dose-response cur ves of each drug in previous experiments) 20 min before uric acid and the a bility of the rat to use the injured hindlimb was recorded with a computeri zed system. The effect produced by each treatment was compared with that ob served after the compounds were administered in the left hindlimb, i.e., co ntralateral administration. The results showed that all three compounds sig nificantly inhibited uric acid-induced dysfunction of the right hindlimb (c ontrol = 64 +/- 8 au; indomethacin = 391 +/- 30 au; MK-966 = 368 +/- 17 au; SC-560 = 445 +/- 25 au, ANOVA, Dunnett's test, P < 0.01). In addition, the results using contralateral administration suggest that the analgesic effe ct was due to inhibition of locally produced COX-1 and COX-2 and, therefore , that no central mechanisms were involved. Taken together, the present dat a using the pain-induced functional impairment model in rats support the id ea that both COX isoforms (1 and 2) contribute to the local inflammatory re sponse in the model and that they may have a role in the maintenance of phy siological homeostasis. They might also suggest that the therapeutic benefi ts of NSAIDs are mainly due to inhibition of both COX isoforms. (C) 2001 Wi ley-Liss, Inc.