Endogenous Modulation of Catecholamine Release

直到大约十年前，人们才相信吗啡和与其密切相关的可待因只由罂粟植物产生，而不是其他植物或动物物种。然而，最近的研究表明，这两种阿片类药物实际上是由包括人类在内的多种动物产生的。在中枢神经系统的某些区域和内分泌器官肾上腺髓质中发现了特别高的浓度。这些令人惊讶的发现提出了内源性阿片类药物功能的问题，也提出了这些阿片类药物如何与阿片类肽相互作用的问题，阿片类肽是一种完全不相关的物质，在神经系统的各个区域和内分泌腺中都很常见。在发现动物产生的阿片类药物之前，人们认为吗啡的心理和镇痛作用是由于作用于通常对内源性阿片肽有反应的器官。现在，将内源性阿片类药物和阿片类药物的具体作用分离开来变得至关重要。没有这些信息，我们将无法清楚地了解可待因和吗啡的治疗和滥用作用的基础。这个问题非常令人困惑，因为某些细胞产生并释放阿片肽和阿片，这反过来又与来自相同细胞和神经元释放的额外调节物质相互作用。Epple博士在美国国家科学基金会（nsf）的支持下进行的研究使用了一种理想的动物模型——美洲鳗鱼的染色质细胞，结果表明，可待因和吗啡在控制阿片肽（脑啡肽）分泌方面相互作用；脑啡肽反过来控制儿茶酚胺（肾上腺素和去甲肾上腺素）的分泌，儿茶酚胺是染色质细胞的实际激素。因此，嗜铬细胞使用影响细胞自身的物质（“自分泌分泌物”）来控制激素的释放，然后这些激素在很大程度上作用于远处的“目标”器官。有趣的是，这些作用发生在远低于治疗或滥用效果所需的阿片浓度的情况下。所提出的研究的具体目的是进一步揭示儿茶酚胺释放控制中的复杂相互作用，特别强调与神经支配的相互作用。预期的数据将再次为神经元和内分泌细胞的自我调节提供“非常规”的见解，因此对基础研究和治疗策略都具有重要意义。＊＊＊

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. ***