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

Abstract

An appropriate animal model for investigation of antiinflammatory analgesic effects of NSAIDs is the pain-induced functional impairment model in the rat (PIFIR model). The PIFIR model provides a model of inflammatory and chronic pain similar to that of clinical gout. We investigated the possible role 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 antinociceptive 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 intraarticular (i.a.) injection of uric acid into the knee joint of the right hindlimb were compared. The antinociceptive efficacy was determined from the area under the curve (AUC) values obtained from the time course of the antinociceptive effect. Animals received vehicle, 100 µg indomethacin, 100 µg SC-560, or 50 µg of MK-966 (these drug doses were selected from dose-response curves of each drug in previous experiments) 20 min before uric acid and the ability of the rat to use the injured hindlimb was recorded with a computerized system. The effect produced by each treatment was compared with that observed after the compounds were administered in the left hindlimb, i.e., contralateral administration. The results showed that all three compounds significantly inhibited uric acid-induced dysfunction of the right hindlimb (control = 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 effect was due to inhibition of locally produced COX-1 and COX-2 and, therefore, that no central mechanisms were involved. Taken together, the present data using the pain-induced functional impairment model in rats support the idea that both COX isoforms (1 and 2) contribute to the local inflammatory response in the model and that they may have a role in the maintenance of physiological homeostasis. They might also suggest that the therapeutic benefits of NSAIDs are mainly due to inhibition of both COX isoforms. Drug Dev. Res. 51:253-259, 2000.