MORPHINE-INDUCED CHANGES IN CYCLIC AMP METABOLISM AND PROTEIN KINASE ACTIVITY IN THE BRAIN

Abstract

The effects of consecutive oral administration of morphine on the cyclic[c]AMP synthesizing system and cAMP dependent protein kinase activity in the cerebral cortex of mice were examined. The administration of morphine (2-4 wk) induced an increase of the cAMP formation by activating adenylate cyclase, whereas responses of the cAMP synthesizing system to biogenic amines (norepinephrine, dopamine and histamine) added in vitro was found to be significantly attenuated in these animals. cAMP dependent protein kinase activity in the cerebral cortex was also increased following a consecutive oral administration of morphine. These changes in the activities of adenylate cyclase and protein kinase were found mainly in crude mitochondrial and/or synaptosomal fractions. Morphine induced decrease in the response of the cAMP synthesizing system to biogenic amines was rapidly reversed, and a significant increase of the cAMP formation in the presence of added norepinephrine compared with that found in morphinized animals was observed following the administration of levallorphan, a narcotic antagonist. The changes in adenylate cyclase and cAMP dependent protein kinase activities were not affected significantly by levallorphan administration. Alterations in activities of cAMP synthesizing system and of cAMP dependent protein kinase may be involved in processes of the formation of morphine dependence. Possible involvement of abrupt increments in the sensitivity of norepinephrine receptor-adenylate cyclase system and a subsequent increase in cerebral cAMP is also suggested as a cause of morphine withdrawal syndrome.