Inhibition of nitric oxide synthase enhances antinociception mediated by mu, delta and kappa opioid receptors in acute and prolonged pain in the rat spinal cord.

Our study was designed to determine involvement of nitric oxide (NO) in the antinociception mediated by mu, delta and kappa opioid receptors in acute and prolonged pain in the rat spinal cord. The effect of intrathecally (i.t.) injected NO synthase inhibitors and opioid receptor agonists was evaluated in acute pain using a tail-flick and a paw pressure tests, and in prolonged pain by quantification the pain-related behavior after peripheral formalin injection. It was found that the neuronal NO synthase inhibitor 7-nitroindazole (50-400 microg), used in inactive doses, dose-dependently enhanced antinociception induced by morphine (0.5 microg) in the tail-flick and paw pressure. Moreover, coadministration of N(G)-nitro-L-arginine methyl ester (50 microg) another NO synthase inhibitor, with morphine (0.05-0.5 microg) as well as with specific agonists of mu ([D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin 0.1-2.5 ng) and delta ([D-Pen(2,5)]enkephalin 0.02-0.5 microg) opioid receptors, enhanced dose-dependent antinociception in the tail-flick and paw pressure. Coadministration of N(G)-nitro-L-arginine methyl ester with specific kappa opioid receptor agonist 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzenacetamid e (10-100 microg), produced antinociception in the paw pressure only. Additionally, N(G)-nitro-L-arginine methyl ester (100 microg) profoundly potentiated the antinociception induced by [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin (0.5, 15 ng) and [D-Pen(2,5)]enkephalin (2, 10 microg) in the dose-related manner in the formalin test. N(G)-nitro-L-arginine methyl ester (100 microg) also enhanced the antinociception induced by 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzenacetamid e (10-100 microg) but only at the last two time points of the second phase of the formalin test. These data show that inhibition of the spinal NO synthase potentiates the mu-, delta- and to a lesser extent, kappa-mediated spinal antinociception in both acute and prolonged pain.