Abstract

The acute administration of morphine, methadone, etorphine, methionine-enkephalin, leucine-enkephalin and some related pharmacologically active peptides to rats produces biphasic effects on the degree of phosphorylation of striatal synaptic plasma membrane (SPM) proteins by endogenous protein kinases in the membranes. At 1 to 5 min after opioid administration, the phosphorylation of several SPM proteins is enhanced, followed at 10 to 20 min by a severe reduction in the rate of phosphorylation of the same proteins. Multiphasic responses follow the initial biphasic response after the injection of some opioids. Naloxone is able to block the agonist effects. The injection of saline or an inactive narcotic isomer has no effect on the phosphorylation of striatal SPM proteins. The administration of other psychoactive drugs such as clonidine or haloperidol also produces changes in phosphorylation, although the patterns of change are distinctly different from those produced by opioids. The proteins affected by opioid administration resemble those susceptible to stimulation of phosphorylation in the presence of Ca++/calmodulin. The role of Ca++/calmodulin-regulated reactions in the mechanisms of action of opioids has been evaluated by the addition of these modulators to the assays of preparation from opioid-treated rats. Neither modulators, added separately or together to the assay, was able to restore a depressed phosphorylation to normal levels, although each modulator was effective in stimulating the phosphorylation of many SPM proteins.