Opiates, cyclic nucleotides, and xanthines.

In rat brain homogenate, opiates exert a dose-related inhibition of PGE-stimulated cyclic (AMP) formation. This effect is stereospecific and is correlated with agonist potency. Naloxone antagonizes heroid in a dose-related way, without, at effective concentrations, itself inhibiting PGE-stimulated cyclic AMP formation. In morphine-dependent rats, intracerebroventricular injection of cyclic AMP intensifies and of dibutyryl cyclic GMP diminishes precipitated abstinence effects. In naive rats, the xanthines, theophylline and 3-isobutyl-1-methylxanthine, produce a quasimorphine-abstinence syndrome that is readily suppressed by heroin and intensified by nalosone. In rat brain homogenate, these xanthines inhibit cyclic AMP phosphodiesterase. These findings are concistent with these views: (a) The opiates specifically inhibit an adenylate cyclase of morphine-sensitive neurons that is sensitive to stimulation by PGEs. (b) Opiate agonist action is associated with the lowering of a neuronal cyclic AMP. (c) Both the morphine-abstinence syndrome in dependent rats and the quasi-abstinence syndrome in naive rats are associated with a rise in this neuronal cyclic AMP. (d) There are two types of endogenous humoral mediator acting on morphine-sensitive neurons, one of which is morphine-like and the other antimorphine-like in action.