The striatum is richly innervated by both enkephalinergic and dopaminergic neurons, providing an anatomic framework from which intimate functional interrelationships between these neuronal systems may be postulated. Accordingly, many functional processes within dopamine neurons have been shown to be modulated by opioid peptides. In the present study we confirm predictable reciprocal effects in enkephalin neurons, brought about by modification of dopamine neurotransmission. Dopamine receptor blockade reliably increased striatal Met-enkephalin concentrations by about 50%, whereas chronic treatment with a potent long-acting dopamine receptor agonist was necessary to demonstrate a small 10-20% decrease in Met-enkephalin concentrations. Depletion of presynaptic dopamine also resulted in a marked 50-60% augmentation of Met-enkephalin levels, that could be prevented by concomitant treatment with a dopamine analogue. Increasing dopamine turnover and release by a mu-opioid agonist decreased Met-enkephalin concentrations, as might have been predicted. Thus we have shown a marked dopaminergic influence that maintains striatal Met-enkephalin concentrations by near maximal tonic inhibitory effects.