Blockade of the antinociception induced by diclofenac, but not of indomethacin, by sulfonylureas and biguanides

There is evidence that administration of sulfonylureas, such as glibenclamide and tolbutamide, blocks diclofenac-induced antinociception, suggesting that diclofenac activates ATP-sensitive K+ channels. However, there is no evidence for the interaction between diclofenac and other hypoglycemic drugs, such as the biguanides metformin or phenformin. Therefore, this work was undertaken to determine whether two sulfonylureas, glibenclamide and glipizide, as well as two biguanides, metformin and phenformin, have any effect on the systemic antinociception that is induced by diclofenac and indomethacin using the rat formalin test as an animal model. Systemic injections of diclofenac (10 to 30 mg/kg) and indomethacin (10 to 30 mg/kg) produced dose-dependent antinociception during the second phase of the test. Systemic pretreatment with glibenclamide (3 and 10 mg/kg), glipizide (3 and 10 mg/kg), metformin (100 and 180 mg/kg) or phenformin (100 and 180 mg/kg) blocked diclofenac-induced systemic antinociception in the second phase of the test (P < 0.05). In contrast, pretreatment with glibenclamide, glipizide, metformin or phenformin did not block indomethacin-induced systemic antinociception (P > 0.05). These data suggest that diclofenac, but not indomethacin, activated K+ channels and metformin and phenformin-dependent mechanisms, which resulted in systemic antinociceptive effects in the rat formalin test.