The inhibitory actions of exogenous noradrenaline (1 microM) and clonidine (1 microM) as well as well as of the opiate receptor agonists morphine (1 microM) and [D-Ala2,D-Leu5]enkephalin (DADLE, 1 microM) on the potassium-induced Ca2+-dependent release of [3H]noradrenaline from superfused rat brain cortex slices were independent of the degree of depolarization when release was effected by 15 or 56 mM K+ for 5 min. The non-depolarization-dependent release of [3H]noradrenaline induced by exposing the slices for 5 min to medium with NaCl replaced by LiCl was only partially Ca2+-dependent and was not inhibited by the Ca2+ antagonist Cd2+ (50 microM). This release was strongly inhibited by morphine, DADLE, exogenous noradrenaline and clonidine at 1 microM concentrations both in the presence and the absence of extracellular Ca2+. Together with other data in the literature these results strongly suggest that opiate receptors and alpha 2-adrenoceptors located on noradrenergic axonal varicosities, unlike those located on cell bodies, do not primarily mediate hyperpolarization of the neuronal membrane. Instead the activation of these presynaptic receptors causes a reduction of Ca2+ availability for, or the utilization of Ca2+ by the secretion process upon invasion of an action potential.