Activation of a NO-cyclic GMP system by NO donors potentiates beta-endorphin-induced antinociception in the mouse

Nitric oxide (NO) donors such as sodium nitroprusside (SNP, 0.01-1 mu g) or 3-morpholino-sydnonimine (SIN-1, 0.1-10 mu g) administered intracerebroventricularly (i.c.v.) produced a dose-dependent potentiation of beta-endorphin-induced antinociception assessed by the tail-flick test in ICR mice. The same i.c.v. treatment with SNP or SIN-1 did not affect the antinociception induced by mu-, delta-, or kappa-opioid receptor agonists. The goal of the present study was to determine if the potentiation of the beta-endorphin-induced antinociception by NO donors is mediated by the activation of a NO-cGMP system. Co-administration of hemoglobin (30-120 mu g) or methylene blue (1.25-5 mu g), but not N(o)mega-nitro-L-arginine (1-5 mu g) with beta-endorphin (0.1 mu g) given i.c.v. dose-dependently attenuated the potentiating effects of SNP or SIN-1 on beta-endorphin-induced antinociception. However, the same i.c.v. treatments of mice with hemoglobin, methylene blue or N(o)mega-nitro-L-arginine did not directly affect the i.c.v. administered beta-endorphin-induced antinociception. On the other hand, the treatment of mice with a combination of NO donor (SNP, 0.1 mu g or SIN-1, 1 mu g) and zaprinast (a cGMP phosphodiesterase inhibitor, 1 mu g) further potentiated beta-endorphin-induced antinociception. These results indicate that the potentiating effect of SNP or SIN-1 on beta-endorphin-induced antinociception is mediated by the increased production of NO-cyclic GMP in the brain. However, the NO-cGMP system is not directly involved in the beta-endorphin-induced antinociception.