Cyclic adenosine monophosphate antagonism of morphine analgesia

The administration of cyclic adenosine 3',5' monophosphate (cAMP) intracerebrally or intravenously antagonized morphine analgesia in nontolerant and tolerant mice. The cAMP surrogates dibutyryl cAMP, a phosphodiesterase resistant cAMP analog, and theophylline, a phosphodiesterase inhibitor, acted in a similar manner. The antagonism of morphine effects by all three compounds persisted for at least 24 hr and may have lasted for 48 hr. Elevation of brain biogenic amines by monoamine oxidase inhibition with pargyline reversed the antagonistic effects of cAMP on morphine analgesia. Increasing brain dopamine with L dopa did not prevent cAMP antagonism of morphine analgesia. Increasing brain serotonin with tryptophan not only failed to reverse the effect of cAMP, but also appeared to enhance the cAMP response. However, elevation of norepinephrine with dihydroxyphenylserine did reverse the antagonistic effect of cAMP. It is included, therefore, that norepinephrine is more important for the reversal of cAMP antagonism of morphine analgesia than either dopamine or serotonin.