Modulation of the reinforcing effects of cocaine and morphine by the kappa-opioid receptor agonist U50,488H (trans-3,4-dichloro-N-methyl-N-(2-1-pyrrolidinyl)-cyclohexyl-benzeace tamide) was studied by using the method of intravenous (i.v.) self-administration in drug-naive Wistar rats and DBA/2 mice. Self-administration of cocaine (by rats) and morphine (by mice) was readily initiated and showed an inverted U-shaped unit dose-response curve. Treatment with the kappa-opioid receptor agonist U50,488H dose dependently decreased the intake of both cocaine and morphine when offered in doses that readily initiated and sustained self-administration behavior. Interestingly, treatment with U50,488H induced self-administration behavior with lower sub-threshold doses of cocaine and morphine. With regard to the inverted U-shaped relation between the dose of the drug and the number of self-infusions, it seems that activation of the kappa-opioid receptor with U50,488H produced an almost parallel shift to the left, indicating an increased sensitivity of the animals for the reinforcing effects of cocaine and morphine. These data demonstrate an involvement of kappa-opioid systems in the neurobiological mechanisms underlying drug addiction in general, and sensitivity for drug reward in particular. Furthermore, the dual effect of kappa-opioid receptor agonists on drug self-administration may prompt further research into the mechanisms underlying the role of endogenous opioids in drug self-administration.