Additive interaction between peripheral and central mechanisms involved in the antinociceptive effect of diclofenac in the formalin test in rats.

It has been proposed that the antinociception of systemic diclofenac is the outcome of peripheral and central actions. Hence, our purpose was to examine if systemic diclofenac is able to achieve effective concentrations at local and spinal sites and to characterize the interaction between its local and spinal actions. Pain was produced in the rat using the formalin test. Oral diclofenac (1-10 mg/kg) reduced formalin-induced pain. The antinociceptive effect of oral diclofenac (10 mg/kg) was abolished by local or spinal administration of either L-NAME (1-100 microg and 1-50 microg) or glibenclamide (12.5-100 microg and 25-75 microg). These results suggest that oral diclofenac achieves effective concentrations producing an antinociceptive effect involving participation of the NO-potassium channel pathway at both, the local and spinal levels. In an additional experimental series, diclofenac was administered either locally (25-200 microg) or spinally (12.5-100 microg), yielding an antinociceptive effect by both routes. Then, diclofenac was given simultaneously by these two routes in a fixed-ratio, and antinociception was assayed. Isobolographic analysis revealed an additive interaction between the local and spinal effects of diclofenac. Hence, our results provide evidence that the overall antinociceptive effect induced by systemic diclofenac is the outcome of central and peripheral mechanisms.