In 1680, the English physician Thomas Sydenham wrote, "Among the remedies which it has pleased Almightly God to give man to relieve his suffering, none is so universal and so efficacious as opium". Over the intervening centuries, the admiration of the medical community for the pain relieving effects of opium and its derivatives has been tempered by an increasing awareness of their toxicity and addictiveness. This, together with the lack of any other known class of drugs that exert the powerful analgesic action of opiates, has stimulated an intensive search for synthetic opiates with the desirable properties of morphine, but without the undesirable sideeffects. More recently, natural morphine-like substances have been found in the brain. These substances promise to open new avenues to an understanding of precisely where in the body opiates act, how they do so and why they are addictive. The general aim of this conference is to discuss drug-related problems and drug dependence. The basic scientist approaches this important field of study by attempting to understand precisely how these drugs affect the organism, and, in the case of opiates, how they interact with the central nervous system (CNS). My intention isto describe some recent advances in opiate research, including some of our own work, and to give an overview of how these affect the problems of dependence. Drugs, hormones and neurotransmitters all produce their effects at very low concentration. It is usually assumed they act at specific receptor sites located on the external surface of cells in the target organs. The notion that some tissues might possess such receptors for opiates is supported by the facts that (1) opiate agonists have similar chemical structure, (2) they are stereospecific in that only the laevo isomers are active, and (3) opiate antagonists can be formed by very slight molecular modifications of agonists. For these reasons, pharmacologists assumed that specific opiate receptors must exist in the brain and possibly in other tissues. In the early 1970s, receptors for opiates were identifed by binding radioactively labelled opiates to fragments of membrane from homogenized brain cells. Not only was this binding shown to be stereospecific, but perhaps more importantly, the affinity or tightness with which a range of agonists bound to the receptor closely paralleled their pharmacological activity. With these techniques it was soon demonstrated that the distribution and density of the opiate receptor in different regions of the CNS corresponded to those regions and pathways believed associated with the sensory and emotional aspects of pain. What are these receptors for opiates doing there? The findings suggested the presence of a natural morphine-like substance in the brain, possibly a neurotransmiffer, that acts at these receptors. The speculafion ended when, in 1975, a remarkable discovery was made w two pentapeptides were isolated from the brain which behaved like opiates in a number of pharmacological tests using peripheral tissues, such as the mouse vas deferens and guinea pig ileum. These actions were stereospecific and were antagonized by naloxone, indicating an action on the opiate receptor. 12 These pentapeptides, with the amino acid sequences of TYR-GLY-GLY-PHE-MET and TYR-GLY-GLY-PHE-LEU, were given the names Methionine- and Leucine-Enkephalin respectively. This sequence was soon recognized by some chemists to be present within the pituitary homone betalipotropin. The enkephalin sequence occurs at positions 61-65 in the 91 amino acid beta-lipotropin molecule, and the C-terminal fragment (amino acids 61-91) was found to be a potent opiate peptide. The term "endorphins" has been applied to the family of larger peptides, the prototype beta-Upotropin 61-91 being called "beta-endorphine" (for review, see Snyder,