Stimmel B, Kreek M J
Graduate Medical Education, Box 1193, Mount Sinai School of Medicine, One East 100th Street, New York, NY 10029-6574, USA.
Mt Sinai J Med. 2000 Oct-Nov;67(5-6):375-80.
Scientific information about the neurobiology of addictive behaviors provides an increasingly important rationale to support opioid agonist pharmacotherapy, primarily methadone maintenance treatment, for long-term heroin addiction. In late 1963 and 1964, the first research was performed at The Rockefeller Institute for Medical Research by Dole, Nyswander, and Kreek in an attempt to develop a new pharmacotherapy for opiate addiction. The hypothesis underlying that research was that heroin addiction was a disease. However, the evidence for heroin addiction being a disease was based primarily on clinical anecdotes and the natural history of opiate addiction. Until then chronic addiction was managed primarily using abstinence-based, medication-free behavioral approaches. Such approaches were uniformly successful in only a small percent of long-term heroin addicts. Subsequent research, both clinical research as well as laboratory-based research, using a variety of appropriate animal models as well as in vitro techniques, has shown that drugs of abuse in general, and specifically the short-acting opiates, such as heroin, may profoundly alter molecular and neurochemical indices, and thus physiologic functions. Also, research has shown that after chronic exposure to a short-acting opiate,these alterations may be persistent, or even permanent, and may contribute directly to the perpetuation of self-administration of opiates, and even the return to opiate use after achieving a drug-free and medication-free state. There is ample evidence now that disruption of several components of the endogenous opioid system, ranging from changes in gene expression to changes in behavior, may occur during cycles of short-acting opiate abuse. Also, there are very convincing studies that suggest that stress responsivity is profoundly altered by chronic abuse of short-acting opiates including: documentation of atypical hypo-responsivity to stressors during cycles of heroin addiction; evidence of sustained hyper-responsivity to stressors in the medication-free, illicit-opiate-free state; and in contrast, normalization of stress responsivity, as reflected by the hypothalamic-pituitary-adrenal axis function in long-term, methadone-maintained patients. Thus, both laboratory and clinical research studies provide firm documentation that the disruption of physiologic, as well as behavioral, functions occurs during chronic administration of short-acting opiates. Also, there is research evidence of an epidemiologic, and more recently of a molecular genetics type, that a genetic vulnerability to develop addictions in general, and opiate addiction specifically, may exist, and that early environmental factors may alter physiology to enhance vulnerability to develop opiate addiction when self-exposed.
关于成瘾行为神经生物学的科学信息为支持阿片类激动剂药物治疗（主要是美沙酮维持治疗）以应对长期海洛因成瘾提供了日益重要的理论依据。1963年末和1964年，多尔、尼斯万德和克里克在洛克菲勒医学研究所开展了首批研究，试图开发一种治疗阿片类成瘾的新药物疗法。该研究的基本假设是海洛因成瘾是一种疾病。然而，海洛因成瘾是一种疾病的证据主要基于临床轶事和阿片类成瘾的自然史。在此之前，慢性成瘾主要通过基于禁欲、无药物的行为方法进行管理。此类方法仅在一小部分长期海洛因成瘾者中取得了一致成功。随后的研究，包括临床研究以及基于实验室的研究，使用了各种合适的动物模型以及体外技术，结果表明，一般而言，滥用药物，尤其是短效阿片类药物，如海洛因，可能会深刻改变分子和神经化学指标，进而影响生理功能。此外，研究表明，在长期接触短效阿片类药物后，这些改变可能会持续，甚至永久存在，并可能直接导致阿片类药物自我给药行为的持续，甚至在达到无毒品和无药物状态后重新使用阿片类药物。现在有充分证据表明，在短效阿片类药物滥用周期中，内源性阿片系统的多个组成部分可能会受到干扰，从基因表达变化到行为改变。此外，有非常有说服力的研究表明，长期滥用短效阿片类药物会深刻改变应激反应性，包括：记录海洛因成瘾周期中对应激源的非典型低反应性；在无药物、无非法阿片类药物状态下对应激源持续高反应性的证据；相反，长期接受美沙酮维持治疗的患者下丘脑 - 垂体 - 肾上腺轴功能反映出应激反应性恢复正常。因此，实验室研究和临床研究均提供了确凿证据表明，在长期使用短效阿片类药物期间，生理功能以及行为功能会受到干扰。此外，有流行病学研究证据，最近还有分子遗传学类型的证据表明，可能存在对一般成瘾，尤其是阿片类成瘾的遗传易感性，并且早期环境因素可能会改变生理机能，从而在个体接触毒品时增加患阿片类成瘾的易感性。
