Lobeline diminishes the behavioral and neurochemical effects of nicotine and amphetamines, and is considered a potential pharmacotherapy for drug abuse and addiction. Lobeline has high affinity for nicotinic acetylcholine receptors and inhibits the function of vesicular monoamine and dopamine transporters. The present study investigated the less-explored interaction of lobeline and the endogenous opioid system. In guinea pig brain homogenates, lobeline displaced (K(i)=0.74 microM) the binding of [(3)H]DAMGO [(D-Ala(2), N-ME-Phe(4), Gly(5)-ol)-enkephalin]. In a functional assay system comprised of MOR-1 mu opioid receptors and GIRK2 potassium channels expressed in Xenopus oocytes, lobeline had no effect on the resting current, but maximally inhibited (IC(50)=1.1 microM) morphine- and DAMGO-activated potassium current in a concentration-dependent manner. In a second functional assay, lobeline-evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine was not blocked by naltrexone. Importantly, concentrations of lobeline (0.1-0.3 microM) that did not have intrinsic activity attenuated ( approximately 50%) morphine-evoked [(3)H]overflow. Overall, the results suggest that lobeline functions as a mu opioid receptor antagonist. The ability of lobeline to block psychostimulant effects may be mediated by opioid receptor antagonism, and lobeline could be investigated as a treatment for opiate addiction.