Multiplicative interaction between intrathecally and intracerebroventricularly administered morphine for antinociception in the mouse: effects of spinally and supraspinally injected 3-isobutyl-1-methylxanthine, cholera toxin, and pertussis toxin.

1. Either intrathecal (i.t.) or intracerebroventricular (i.c.v.) administration of morphine alone at the dose of 0.2 microgram slightly increased inhibition of the tail-flick response. However, combined i.t. and i.c.v. injections of morphine at the same dose increased the inhibition of the tail-flick response in a synergistic manner. 2. Cholera toxin (CTX, 0.05 to 0.5 microgram) pretreated i.t. or i.c.v. for 24 hr or pertussis toxin (PTX, 0.05 to 0.5 microgram) for 6 days dose-dependently attenuated inhibition of the tail-flick response induced by combined i.t. and i.c.v. injection of morphine. 3. 3-Isobutyl-1-methylxanthine (IBMX, 0.001 to 0.1 ng) pretreated i.t. for 10 min dose-dependently attenuated the inhibition of the tail-flick response induced by combined i.t. and i.c.v. injections of morphine. However, IBMX pretreated i.c.v. for 10 min was not effective in attenuating the inhibition of the tail-flick response induced by combined i.t. and i.c.v. injections of morphine. 4. It is concluded that both spinal and supraspinal CTX- and PTX-sensitive G-proteins are involved in the antinociception produced by morphine-induced multiplicative interaction between spinal and supraspinal sites. However, only spinal but not supraspinal cAMP phosphodiesterase is involved in mediating antinociception induced by morphine-induced multiplicative interaction.