Cardinali Daniel P, Golombek Diego A, Rosenstein Ruth E, Brusco Luis I, Vigo Daniel E
BIOMED-UCA-CONICET and Department of Teaching and Research, Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina; Laboratory of Retinal Neurochemistry and Experimental Ophthalmology, Department of Human Biochemistry, School of Medicine/CEFyBO, University of Buenos Aires/CONICET, Buenos Aires, Argentina.
Department of Science and Technology, National University of Quilmes and CONICET, Argentina; Laboratory of Retinal Neurochemistry and Experimental Ophthalmology, Department of Human Biochemistry, School of Medicine/CEFyBO, University of Buenos Aires/CONICET, Buenos Aires, Argentina.
Pharmacol Res. 2016 Jul;109:12-23. doi: 10.1016/j.phrs.2015.08.016. Epub 2015 Oct 9.
The abuse of benzodiazepine (BZP) and Z drugs has become, due to the tolerance and dependence they produce, a serious public health problem. Thirty years ago, we demonstrated in experimental animals the interaction of melatonin with central BZD receptors, and in 1997 we published the first series of elderly patients who reduced BZP consumption after melatonin treatment. Almost every single neuron in the hypothalamic suprachiasmatic nuclei (SCN), the central pacemaker of the circadian system, contains γ-aminobutyric acid (GABA) and many results in animals point out to a melatonin interaction with GABA-containing neurons. In addition, central-type BZD antagonism, that obliterates GABAA receptor function, blunted most behavioral effects of melatonin including sleep. Melatonin is involved in the regulation of human sleep. This is supported by the temporal relationship between the rise of plasma melatonin levels and sleep propensity as well as by the sleep-promoting effects of exogenously administered melatonin. Both meta-analyses and consensus agreements give support to the therapeutic use of melatonin in sleep disorders. This action is attributed to MT1 and MT2 melatoninergic receptors localized in the SCN, as well as in other brain areas. This review discusses available data on the efficacy of melatonin to curtail chronic BZD/Z drug use in insomnia patients. A major advantage is that melatonin has a very safe profile, it is usually remarkably well tolerated and, in some studies, it has been administered to patients at very large doses and for long periods of time, without any potentiality of abuse. Further studies on this application of melatonin are warranted.
由于苯二氮䓬（BZP）和Z类药物会产生耐受性和依赖性，其滥用已成为一个严重的公共卫生问题。30年前，我们在实验动物中证明了褪黑素与中枢苯二氮䓬受体的相互作用，1997年我们发表了首批系列老年患者的数据，这些患者在接受褪黑素治疗后减少了BZP的用量。几乎下丘脑视交叉上核（SCN）中的每一个神经元，即昼夜节律系统的中央起搏器，都含有γ-氨基丁酸（GABA），动物实验的许多结果指出褪黑素与含GABA的神经元存在相互作用。此外，中枢型苯二氮䓬拮抗剂会消除GABAA受体功能，减弱包括睡眠在内的褪黑素的大多数行为效应。褪黑素参与人类睡眠的调节。血浆褪黑素水平升高与睡眠倾向之间的时间关系以及外源性给予褪黑素的促睡眠作用都支持了这一点。荟萃分析和共识意见都支持褪黑素在睡眠障碍中的治疗应用。这种作用归因于位于SCN以及其他脑区的MT1和MT2褪黑素能受体。本综述讨论了褪黑素减少失眠患者长期使用BZP/Z类药物有效性的现有数据。一个主要优点是褪黑素具有非常安全的特性，通常耐受性非常好，并且在一些研究中，已以非常大的剂量和长时间给予患者，没有任何滥用的可能性。有必要对褪黑素的这种应用进行进一步研究。
