9408427 Epple Until about a decade ago, it was believed that morphine and the closely related codeine are only produced by the poppy plant, and no other plant or animal species. However, recent research revealed that both opiates are actually produced by a variety of animals, including the human. Particularly high concentrations were found in certain regions of the central nervous system and in an endocrine organ, the adrenal medulla. These surprising findings raised the question of the functions of the endogenous opiates, and they also raised the question how these opiates interact with the opioid peptides, totally unrelated substances which are common in various reigons of the nervous system, and in endocrine glands. Before the discovery of animal-produced opiates, it was assumed that the psychological and analgesic effects of morphine were due to actions on organs that normally respond to endogenous opioid peptides. Now, it has become critical to separate the specific actions of the endogenous opiates and opioids from each other. Without this information, we will not clearly understand the basis of the therapeutic and abusive effects of both codeine and morphine. The issue is very confusing since certain cells produce and release both opioid peptides and opiates, which in turn interact with additional regulatory substances released from the same cells and from neurons. Using an ideally suited animal model, the chromaffin cells of the American eel, Dr. Epple's NSF-supported research has shown, inter alia, that codeine and morphine interact with each other in the control of opioid peptide (enkephalin) secretion; and that enkephalin, in turn, controls the secretion of catecholamines (adrenaline and noradrenaline) which are the actual hormones of the chromaffin cells. Thus, the chromaffin cells use substances that affect the cells themselves ("autocrine secretions") to control release of hormones which then largely act on distant "target" organs. In teresingly, these actions occur at opiate concentrations that are far below those needed for therapeutic or abusive effects. The specific aim of the proposed investigations is to further unravel the complex interactions in the control of catecholamine release, with particular emphasis on the interaction with the innervation. The expected data should provide once more "unconventional" insights into the self- regulations of both neurons and endocrine cells, and thus have important implications for both basic research and therapeutic strategies. ***
