The unambiguous demonstration of opioid receptor types, and their endogenous ligands, the endorphins, together with a diverse range of synthetic ligands, has created exciting opportunities for research highly relevant to drug abuse. One major objective of this project is to continue the process of defining new opioid receptor subtypes. This process is optimally accomplished by synergistic collaborations with medicinal chemists to develop (a) selective high affinity ligands for each subtype (b) irreversible ligands with receptor subtype specificity and (c) enantiomeric pairs of these ligands for detection of receptor mediated effects. Delta receptor antagonists attenuate alcohol consumption, block morphine tolerance and dependence and decrease cocaine-reinforcement. . Recent work has further delineated two subtypes of the delta binding site, and provided new information about subtypes of the delta-cx subtype. The determination of delta receptor subtypes may lead to new medicines for the treatment of alcoholism and drug addiction. Collaborative efforts with Dr. Rice's lab have led to the identification and biological evaluation of highly selective nonpeptide delta agonists. Other studies with the cloned opioid receptor indicated that potency, efficacy and intrinsic efficacy may be mediated by different binding domains. Converging lines of investigation suggest that kappa receptor antagonists may be useful for the treatment of depression, anxiety, psychosis and craving. Previous demonstrated up to four subtypes of kappa opioid receptors in rat, guinea pig and human brain, suggesting that it may be possible to develop kappa agonists devoid of psychotomimetic side effects. More recent studies using the novel radioligand [125I]IOXY showed that kappa2 receptors are up-regulated by cocaine in fatal overdose victims. The notion that dysfunction of the CNS opioid receptor/endorphin system contributes to drug abuse was tested in an open-label study of buprenorphine combined with naltrexone.