Interaction of inducible nitric oxide synthase and cyclooxygenase-2 inhibitors in formalin-induced nociception in mice

Studies with inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 inhibitor were conducted to assess their synergistic antinociceptive effect and possible therapeutic advantage. The antinociceptive interaction of rofecoxib, a selective cyclooxygenase-2 inhibitor, with aminoguanidine hydrochloride, a selective iNOS inhibitor, was examined in the formalin-induced paw-licking model in mice. Analysis of variance (ANOVA) and the isobolographic method were used to identify the nature of the antinociceptive interaction. Different doses of rofecoxib (1, 3, 10 and 30 mg/kg) and aminoguanidine hydrochloride (10, 30, 100 and 300 mg/kg) alone were administered orally to adult male albino mice (20-30 g). Only high doses of rofecoxib (10 and 30 mg/kg) and aminoguanidine hydrochloride (100 and 300 mg/kg) showed a statistically significant antinociceptive effect. Combination of a subthreshold dose of rofecoxib (1 mg/kg) with increasing doses of aminoguanidine hydrochloride (30, 100 and 300 mg/kg) resulted in potentiated antinociception (P<0.05). Combined therapy with a subthreshold dose of aminoguanidine hydrochloride (30 mg/kg) with increasing doses of rofecoxib (1, 3, 10 and 30 mg/kg) also resulted in significant antinociception (P<0.05). These results suggest that rofecoxib and aminoguanidine hydrochloride act synergistically in their antinociceptive action in mice. A possible mechanism of interaction is that nitric oxide (NO) stimulates the activity of cyclooxygenase-2 by combining with its heme component. Furthermore, the present results suggest that combination therapy with rofecoxib and aminoguanidine hydrochloride may provide an alternative for the clinical control of pain. (C) 2004 Elsevier B.V. All rights reserved.