Pain-induced functional impairment in the rat (PIFIR) is a model of inflammatory and arthritic pain similar to that of clinical gout. Nociception is induced by the intra-articular injection of uric acid into the right hind limb, inducing its dysfunction. Animals then receive analgesic drugs and the recovery of functionality over time is assessed as an expression of antinociception. We have examined the role of peripheral prostaglandins synthesized by cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in inflammatory pain using the PIFIR model. Rofecoxib (a selective COX-2 inhibitor) and SC-560 (a selective COX-1 inhibitor) both produced dose-dependent effects. When the inhibitors were administered before uric acid, they showed similar potency, but the antinociceptive efficacy of SC-560 was lower than rofecoxib; the best antinociceptive effects were obtained with the dose of 100 microg/articulation of each inhibitor (pre-treatment). In post-treatment (inhibitors administered after the uric acid), rofecoxib showed the least antinociceptive effect and SC-560 was more potent than rofecoxib. The inhibition of both COX-1 and COX-2 produced a more profound analgesic effect than the inhibition of either COX-1 or COX-2 alone. The present data support the idea that both COX isoforms contribute to the development and maintenance of local inflammatory nociception. Thus, it could be expected that inhibition of both COX-1 and COX-2 is required for non-steroidal anti-inflammatory drugs (NSAID)-induced antinociception in the rat. These findings suggest that the therapeutic effects of NSAIDs may involve, at least in part, inhibition of COX-1 and COX-2.

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In the present study, the analgesic efficacy and the possible development of tolerance produced by the combination metamizol+morphine (562.3:5.6 mg/kg) during subchronic treatment (6 and 12 days) in arthritic rats using the PIFIR model was evaluated. This combination of metamizol+morphine produced the maximum analgesic efficacy (AUC E = 353.4 ± 24.7 au) when compared with morphine 5.6 mg/kg (AUC E = 196.6 ± 35.3 au), metamizol 562.3 mg/kg (AUC E = 262.8 ± 10.2 au), and morphine 10 mg/ kg (AUC E = 316.6 ± 31.0 au) given in a single dose. The results were essentially the same when the combination was administered for 6 (AUC E = 325.4 ± 13.1 au) or 12 days (AUC E = 354.5 ± 9.6 au). In addition, the duration of the effect was longer when the combination metamizol+morphine was administered either in single or subchronic treatment. Development of tolerance to the analgesic effect was observed after 6 and 12 days of morphine administration. However, the analgesic effect produced by the metamizol+morphine combination remained constant (near 100%) during both subchronic treatments. The present data demonstrate that metamizol significantly attenuates the development of tolerance to morphine. The mechanism involved in this effect of metamizol remains to be determined. Drug Dev. Res. 51:260-267, 2000.