Mechanisms of dopamine antagonism by morphine in rodents

A number of investigators have concluded on the basis of a substantial and compelling body of biochemical, pharmacological and behavioral evidence, that opiates and particularly morphine, directly block central dopamine (DA) receptors. This evidence includes the recent finding that cataleptogenic doses of morphine suppress 3H-spiroperidol binding to striatal membranes ex vivo. On the other hand, an important albeit relatively sparse literature of experimental evidence exists suggesting that morphine and other mu-receptor opiates do not directly bind to central dopaminergic receptors. The most convincing evidence to this effect are behavioral findings that morphine potentiates rather than inhibits the stereotyped behavior induced by the direct DA agonist apomorphine and biochemical evidence demonstrating a failure of 3H-morphine or 3H-dihydromorphine to specifically bind central DA receptors in striatal tissue. (Indeed, even those reports that demonstrated a morphine induced suppression of 3H-spirioperidol labelling of DA receptors failed to find a direct effect on post-synaptic receptors.) Evidence is presented in this report to show that morphine acts presynaptically to acutely inhibit DA release, and thus, that morphine inhibition of DA receptor mediated responses is indirect, being the result of an inhibition of pre-synaptic DA release rather than a direct effect exerted on post-synaptic DA receptors themselves.