Self-synergy antinociceptive effect of diclofenac: effect of peripheral inhibition of nitric oxide synthase.

Abstract

This study was conducted to characterize the interaction between the systemic and local peripheral antinociceptive effect of diclofenac, a nonsteroidal anti-inflammatory drug. As well as the effect of local peripheral administration of NG-nitro-L-arginine methyl ester (L-NAME) - a nitric oxide synthesis inhibitor - on the antinociceptive effect of diclofenac. The antinociceptive effect of diclofenac in a fixed-ratio combination of local or intraperitoneal delivery diclofenac was evaluated using the formalin test. Pain-related behavior was quantified in terms of the number of flinches of the injected paw with formalin. Isobolographic analysis was employed to characterize the interaction between the two routes. ED30 values were estimated for each route, and an isobologram was constructed. Diclofenac and its fixed-ratio combination produced a dose-dependent antinociceptive effect in the second phase, but not in the first phase of the formalin test. The analysis revealed that the simultaneous administration of diclofenac through the two routes was synergistic. Pretreatment of the injured paw with L-NAME partially blocked local, systemic, and simultaneous local and systemic diclofenac-induced antinociception. The obtained results show a synergism after simultaneous administration of diclofenac through two different routes. In addition, it is found that either the local or systemic antinociceptive effect of diclofenac involves the activation of the nitric oxide pathway at the peripheral level.