KAPPA-OPIOID RECEPTOR AGONIST U50,488H MODULATES COCAINE AND MORPHINESELF-ADMINISTRATION IN DRUG-NAIVE RATS AND MICE

Modulation of the reinforcing effects of cocaine and morphine by the k appa-opioid receptor agonist U50,488H (trans-3,4-dichloro-N-methyl-N- (2-1-pyrrolidinyl)-cyclohexyl-benzeacetamid was studied by using the m ethod of intravenous (i.v.) self-administration in drug-naive Wistar r ats and DBA/2 mice. Self-administration of cocaine (by rats) and morph ine (by mice) was readily initiated and showed an inverted U-shaped un it dose-response curve. Treatment with the kappa-opioid receptor agoni st U50,488H dose dependently decreased the intake of both cocaine and morphine when offered in doses that readily initiated and sustained se lf-administration behavior. Interestingly, treatment with U50,488H ind uced self-administration behavior with lower sub-threshold doses of co caine and morphine. With regard to the inverted U-shaped relation betw een the dose of the drug and the number of self-infusions, it seems th at activation of the kappa-opioid receptor with U50,488H procuced an a lmost parallel shift to the left, indicating an increased sensitivity of the animals for the reinforcing effects of cocaine and morphine. Th ese data demonstrate an involvement of kappa-opioid systems in the neu robiological mechanisms underlying drug addiction in general, and sens itivity 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 endogenou s opioids in drug self-administration.