阿片类药物耐受和依赖机制研究进展

目的:综述了近年来阿片类药物耐受和依赖机制研究进展.方法:以国内外研究阿片类药物耐受和依赖机制有关的代表性论文为依据,进行分析、整理和归纳.结果:中枢多部位、多系统、多途径、多递质、多信号传导通路以及多基因参与了阿片类药物耐受和依赖的形成过程.结论:阿片类药物耐受和依赖是一个复杂的过程,不能将任意一个环节孤立起来.它是今后亟待解决的问题.     

阿片受体与丝裂原活化蛋白激酶信号交联及其对阿片耐受与依赖的影响

中枢神经系统主要存在 μ、δ、κ阿片受体以及新发现的阿片受体样 - 1(ORL - 1)受体。阿片受体急性激活时激活Gi o蛋白 ,三磷酸鸟苷 (GTP)置换Gα结合的三磷酸鸟苷 (GDP)后 ,Gα与 βγ亚单位解离 ,它们分别作用于下游多个效应分子 ,可调节腺苷酸环化酶和磷酯酶C(PLC)的活性 ,激活K +通道 ,抑制Ca2 + 通道并增加胞内Ca2 + 浓度。阿片长期作用于机体后可产生严重的耐受和依赖 ,伴随有神经系统细胞和分子水平的功能以及基因表达的改变[1] 。1996年LiLY等报道了激活阿片受体可将丝裂原活化蛋白激酶 (mitogen -activatedproteinkinase…     

NO 与阿片依赖和耐受

ＮＯ与阿片依赖和耐受陈军郑继旺（北京医科大学中国药物依赖性研究所，北京１０００８３）中国图书分类号Ｒ９７１一氧化氮（ＮＯ）在体内是一种含自由基的气体，易扩散，不稳定，半衰期仅数秒。其在神经系统中的作用目前正越来越受到人们的重视〔１〕。研究表明ＮＯ在中...     

一氧化氮参与阿片耐受和依赖的机制

一氧化氮（NO）作为一种信号的传递因子，参与对阿片耐受和依赖的调节，阿片耐受和依赖时，神经元内NO水平升高，NO可通过NO－环磷酸鸟苷和NO－多聚二磷酸腺苷合酶等多种途径影响阿片耐受和依赖的形成，NO与阿片系统之间的相互调控的机制很复杂，目前尚不完全清楚。     

阿片类药物依赖的治疗学进展

介绍阿片类物质依赖的主要药物治疗学进展，主要包括三个步骤，重点介绍阿片受体激动药和非阿片受体激动药的使用，此外尚有非药物疗法及免疫疗法等。     

抗阿片依赖药物干预的研究进展

人类疾病谱正面临着重大的变化，21世纪上半叶将进入精神疾病时代。在众多的精神疾病中，精神活性物质依赖占有重要位置。其中以阿片类药物造成的滥用最为严重。精神活性物质依赖对国民经济、人口素质和社会安全的危害无法估量。毒瘾是一种病，吸毒者是一类特殊的病人。研究精神活性物质依赖的生物学基础和医学生物学干预手段反应了我国社会和科学发展的重大需求。阿片类毒品危害之所以如此严重主要原因是复发造成的难以戒除，复发主要是由精神依赖引起的，而精神依赖的神经生物学本质又是由于在阿片类毒品长期作用下机体的阿片受体作用系统在受体前、受体上和受体后发生了代偿性适应造成的。目前，在临床上用于脱毒和防复发的医学生物学干预手段主要包括药物干预手段，如激动剂美沙酮、部分激动剂丁丙喏啡和拮抗剂纳曲酮等；生理干预手段，如电针抗复发等。这些干预手段的共同特点都是通过影响阿片受体作用系统的功能实现的。近十多年来，人们逐渐认识到，阿片所导致的代偿性适应不仅和阿片受体作用系统相关，还和多类非阿片受体作用系统密切相关。这些系统至少包括单胺、兴奋性氨基酸、GABA、乙酰胆碱和咪唑啉等受体作用系统。干预这些非阿片受体作用系统的化合物能否成为有效的抗阿片复发药物已成为了本领域新的研究热点。     

阿片类药物对NG108-15细胞Ca~(2 )/钙调蛋白依赖的蛋白激酶II信息通路的作用

目的　观察阿片类依赖时Ca2 钙调蛋白依赖的蛋白激酶II信息通路的变化。方法　以NG10 8 15细胞作为体外的细胞模型 ,分别用竞争性蛋白结合法及放射免疫法、PDE法、γ 32 P参入法测定cAMP水平、钙调蛋白(CaM)活性和钙调蛋白依赖的蛋白激酶II(CaMKII)活性。结果　DPDPE作用NG10 8 15细胞 48h可使细胞浆和细胞核CaM和CaMKII活性升高 ,该变化可被CaM特异性拮抗剂W 7所抑制 ;CaMKII特异性抑制剂KN 6 2可抑制CaMKII活性的增高 ,而对CaM活性无明显影响。DPDPE作用NG10 8 15细胞 48h后 ,加入纳洛酮 ,CaM活性、CaMKII活性进一步增高。结论　Ca2 CaMKII信息通路参与了阿片依赖的机制。     

阿片类药物依赖中存在的性别差异及性激素的作用机制

文献报道在大鼠吗啡的镇痛作用和吗啡耐受中存在性别差异[1],在吗啡诱导的条件性位置偏爱中也存在性别差异[2].大量临床流行病学资料表明,阿片类物质影响人体性腺功能,女性吸毒者常有月经异常、妊娠功能低下、性功能障碍等.另外,使用滥用药物的男性大约是女性的2倍.关于性别差异和性激素在阿片类药物反应中的作用的研究越来越受到重视,揭示与此有关的机制可以对缓解疼痛和对药物滥用的治疗提供更合适的途径.性别差异和阿片类药物依赖之间的相关研究国内报道少见,本文综述了国外一些有关的研究进展情况.     

Acute opioid dependence: characterizing the early adaptations underlying drug withdrawal

RATIONALE: While opioid withdrawal is typically studied under conditions of chronic (i.e., continuous) drug administration, withdrawal signs can also be demonstrated in both humans and animals after a single opioid exposure. This phenomenon, termed acute dependence, may be useful in understanding the early stages of opioid dependence and addiction. OBJECTIVE: This review provides an overview of acute dependence by comparing withdrawal from acute and chronic opioid exposure across dimensions ranging from symptomatology to neural substrates. Assessment of repeated withdrawals from acute opioid administration is also presented as a tool for better understanding the adaptive changes induced by multiple drug exposures. CONCLUSIONS: Although not identical phenomena, acute and chronic dependence share a number of characteristics. Examining potentiations of withdrawal severity across multiple acute opioid exposures may be especially valuable in characterizing the development of drug dependence. Further study of acute dependence promises to lead to more effective treatments for opioid withdrawal and addiction.     

Opioids: cellular mechanisms of tolerance and physical dependence

Morphine and other opioids are used and abused for their analgesic and rewarding properties. Tolerance to these effects develops over hours/days to weeks, as can physical and psychological dependence. Despite much investigation, the precise cellular mechanisms underlying opioid tolerance and dependence remain elusive. Recent studies examining mu-opioid receptor desensitization and trafficking have revealed several potential mechanisms for acute receptor regulation. Other studies have reported changes in many other proteins that develop during chronic opioid treatment or withdrawal and such changes may be partly responsible for the cellular and synaptic adaptations to prolonged opioid exposure. While these studies have added to our knowledge of the cellular processes participating in opioid tolerance and dependence, the challenge remains to integrate these observations into a coherent explanation of the complex changes observed in whole animals chronically exposed to opioids.     

Development of acute opioid tolerance and dependence in rat striatal neurones

Summary Striatal neurones in the rat were frequently observed to develop tachyphylaxis to the specific, naloxone-antagonisable depressant effects of methionine-and leucine-enkephalin on spontaneous and L-glutamate-evoked activity. This loss of responsiveness to the enkephalins occurred within a few minutes of the repeated or prolonged application of these peptides and is suggested to reflect a form of acute tolerance. As with chronic opiate tolerance, the acute tolerance of single striatal neurones to the enkephalins appeared to be associated with dependence on these opioids, as evinced by the withdrawal-like hyperactivity that occurred upon terminating the application of the peptides or upon the microelectrophoresis of naloxone.     

ABCB1基因多态性对阿片类药物依赖和镇痛耐受的影响及机制

药物依赖是当前神经科学研究的热点问题,其病因错综复杂。近年来,药物依赖与ATP结合盒B亚家族成员1转运蛋白(ATP-binding cassette subfamily B member 1 transporter,ABCB1)基因多态性的关系越来越受到关注,特别是位于26号外显子区域的3435C>T。该文就阿片类药物依赖和镇痛耐受与ABCB1基因多态性的关系进行综述,对于深入阐明药物依赖的机制以及指导美沙酮个体化治疗具有重要意义。     

Amiloride inhibits the protein tyrosine kinases associated with the cellular and the transforming src-gene products

Amiloride inhibits a protein tyrosine kinase from rat brain extracts. The kinase activity is characterized by an anti-serum (TBR-serum) which immunoprecipitates pp60c-src, the cellular counterpart of the transforming protein pp60v-src of Rous sarcoma virus. In immunocomplexes, TBR-IgG serves as an artificial but specific phosphate acceptor. The phosphate incorporation into TBR-IgG is a time- and temperature-dependent process. In the presence of amiloride the TBR-IgG phosphorylation is reduced. The drug does not influence the immunocomplexes formed by TBR-IgG and pp60src and no amiloride-activated protein tyrosine phosphatase can be detected in the immunocomplex system. Half-maximal inhibition of the tyrosine kinase occurs at 300 microM amiloride and is competitive with respect to ATP. Viral pp60src kinase of transformed cells is more sensitive to amiloride (IC50: 50-100 microM). Furthermore, normal cellular tyrosine kinases are to a lesser extent inhibited by amiloride as compared to the transforming viral pp60src kinase. These results may indicate different amiloride-sensitive forms of cellular pp60src kinases.     

Drugs used in the treatment of opioid tolerance and physical dependence: a review

Opioid drugs used in the treatment of severe pain are known to produce tolerance that requires a dose increase to maintain a sufficient analgesic effect. As this is connected with side effects such as respiratory depression, it is highly desirable to avoid or at least attenuate the development of tolerance. Closely related, but in some respect dissociable, is the phenomenon of physical dependence, which becomes apparent particularly in heroin withdrawal. Our knowledge about the mechanisms underlying tolerance has increased dramatically in recent years, but a final picture of the importance of each particular mechanism under in vivo conditions has not yet emerged. Recent studies suggest that the so-called receptor down-regulation is not the main mechanism in vivo. A desensitization on the basis of receptor decoupling, receptor internalization and increased alternative coupling to stimulatory G-proteins have been demonstrated. However, a functional antagonism of the opioid effects seems to be clinically most important, mediated by the activation of NMDA receptors, up-regulation of adenylyl cyclase and nitric oxide synthase. Drugs blocking these mechanisms are the most promising option in the treatment of tolerance. Namely, alpha2-adrenoreceptor agonists such as clonidine and NMDA antagonists such as ketamine or dextromethorphan have been used to minimize tolerance development during opioid treatment. Moreover, clinical strategies such as opioid rotation and multimodal analgesia, i.e. the simultaneous application of several analgetics of different type, have proven to be successful approaches.