Morphine-induced changes in cyclic AMP metabolism and protein kinase activity in the brain.

The effects of consecutive oral administration of morphine on the cyclic AMP synthesizing system and cyclic AMP dependent protein kinase activity in the cerebral cortex of mice were examined. The administration of morphine (2--4 weeks) induced an increase of the cyclic AMP formation by activating adenylate cyclase, whereas responses of the cyclic AMP synthesizing system to biogenic amines (norepinephrine, dopamine and histamine) added in vitro was found to be significantly attenuated in these animals. Cyclic AMP 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 cyclic AMP synthesizing system to biogenic amines was rapidly reversed, and a significant increase of the cyclic AMP formation in the presence of added norepinephrine compared with that found in morphinized animals was observed following the administration of levallorphan, a narcotic antagonist. On the other hand, the changes in adenylate cyclase and cyclic AMP dependent protein kinase activities were not affected significantly by levallorphan administration. These results suggest that alterations in activities of cyclic AMP synthesizing system and of cyclic AMP 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 cyclic AMP is also suggested as a cause of morphine withdrawal syndrome.