防复吸新药噻吩诺啡的研究

一个理想的防复吸治疗药物，不但能阻滞毒品与阿片受体结合，防止吸毒成瘾，而且能有效地缓解稽延症状，减少心理渴求；且自身依赖潜能小（或没有依赖），不良反应少，长期服用不耐受，使用方便易得，顺应性好。在现有的防复吸治疗药物和措施中，只有阿片受体部分激动剂有可能同时具有以上特点。噻吩诺啡是我所设计合成的，具有自主知识产权的新型阿片受体部分激动剂，     

药物成瘾治疗新动向

阿片类药物成瘾防复吸一直是作为困扰世界医学界的主题,目前临床上采用阿片类受体激动剂美沙酮、半激动半拮抗剂丁丙喏啡梯度递减替代治疗方案,阿片类药物导致的躯体依赖已经得以解决,临床脱毒基本完成。但吸毒患者复吸率依然很高,导致复吸的因素很多,主要是稽延性症状、心瘾及环境因素,针对复吸原因,许多科研人员正投入大量的工作以研究防复吸的新途径。本文主要介绍药物成瘾治疗的一些新动向。1 阿片类药物受体拮抗剂纳曲酮的应用纳曲酮为纯阿片受体拮抗剂,通过阻断外源性阿片类物质与阿片受体结合,抑制阿片类药物对阿片受体的强化作用,从…     

胍丁胺抗阿片依赖研究进展

阿片成瘾,又称为阿片依赖,是一种慢性复发性脑疾病,可引起一系列严重的社会、经济和公共卫生问题。由于阿片依赖的神经生物学机制尚未阐明,目前仍缺乏有效的医学干预手段。研究阿片依赖的神经生物学机制、寻找有效的防复吸药物已成为阿片依赖研究领域的热点。胍丁胺是一种新发现的候选神经递质或调质,被认为是咪唑啉受体的内源性配体,本文主要以我们的研究工作为基础,对外源性胍丁胺的抗阿片依赖作用特点及其可能的作用机制加以综述。     

纳曲酮使用中的问题和经验

纳曲酮是阿片受体纯拮抗剂,对μ－,δ－,κ－阿片受体均有阻断作用。因而它能阻断再吸毒品时的效应,从而减弱正性强化作用和负性强化作用,在防复吸中起到良好的辅助作用。但导致复吸的原因是复杂的。诸如心理渴求、稽延症状、环境诱惑和负性生活事件等都会导致复吸,而纳曲酮对此则无能为力。纳曲酮应用的成败关键是患者的戒毒决心,家属的监督执行,环境诱惑的摆脱,生活事件的改善,经济条件的许可,稽延症状的治疗和心理行为的矫治。必须采取综合治理的措施,才能更好地发挥纳曲酮的作用。     

防阿片复吸先导化合物和新药的发现

根据国内外现有的研究结果,防海洛因复吸药物的研究主要集中在两个方面。其一是以阿片受体为靶标的防复吸药物研究,其二是以非阿片受体作用系统为靶标的防复吸药物研究。后者将成为防海洛因复吸药物的研究重点。     

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。     

戒毒药物的研究进展

综述了国内外戒毒药物的研究进展，对毒品成瘾性的理论基础和近几年来戒断症状的治疗等作一总结。介绍了成瘾机制、检测方法、诊断药物、治疗药物（包括阿片受体激动剂、非阿片受体激动剂、中医戒毒药物）、预防复吸药物。     

防复吸药物的研究进展

阿片类药物依赖复吸率高达90％以上。世界卫生组织专家认为,阿片类药物依赖是一种反复发作的脑疾病。临床实践证明药物维持治疗是防止阿片类药物依赖复吸的有效方法,药物的干预可以抑制渴求,减少觅药行为的发生。从药理作用角度,防止复吸的药物有二类,一是阿片受体拮抗剂如纳曲酮等,另一种是阿片受体的激动剂或部分激动剂如美沙酮或丁丙诺啡等。本文就已有的相关药物和制剂及其国内目前研发进展介绍如下：     

N-乙酰半胱氨酸:一种治疗药物成瘾和复吸的候选化合物

抗药物成瘾和复吸的药物研发一直是成瘾研究的热点,迄今具有抗成瘾和复吸作用的药物仍较少。乙酰半胱氨酸具有抗氧化作用,在中枢神经系统作用于胶质细胞的胱氨酸/谷氨酸转运体,提高突触间隙的谷氨酸浓度,间接地调控谷氨酸能和多巴胺能神经通路。临床研究发现,乙酰半胱氨酸具有抗成瘾药物复吸作用,是治疗药物成瘾的候选药物。本文主要综述了乙酰半胱氨酸调控药物依赖通路的作用机制,系统总结了乙酰半胱氨酸抗药物复吸的临床研究,以期为乙酰半胱氨酸的临床应用和开发提供依据和思路。     

噻喏啡长效机制的研究

噻喏啡（Thenorphine）是我所设计合成的，最具特色的一个阿片受体部分激动剂。不仅具有激动、拮抗双重效应，而且抗吗啡作用的t1／2长达14天。在动物试验中不仅能抑制吗啡依赖的形成，而且能对抗脱毒后动物的吗啡点燃效应（即复吸）。自身无明显依赖潜能，安全系数大。有可能成为我国第一个具有自主知识产权的、安全有效的防复吸新药。     

Novel approaches for the treatment of psychostimulant and opioid abuse – focus on opioid receptor-based therapies

Introduction: Psychostimulant and opioid addiction are poorly treated. The majority of abstinent users relapse back to drug-taking within a year of abstinence, making ‘anti-relapse’ therapies the focus of much current research. There are two fundamental challenges to developing novel treatments for drug addiction. First, there are three key stimuli that precipitate relapse back to drug-taking: stress, presentation of drug-conditioned cue, taking a small dose of drug. The most successful novel treatment would be effective against all three stimuli. Second, a large number of drug users are poly-drug users: taking more than one drug of abuse at a time. The ideal anti-addiction treatment would, therefore, be effective against all classes of drugs of abuse.

Areas covered: In this review, the authors discuss the clinical need and animal models used to uncover potential novel treatments. There is a very broad range of potential treatment approaches and targets currently being examined as potential anti-relapse therapies. These broadly fit into two categories: ‘memory-based’ and ‘receptor-based’ and the authors discuss the key targets here within.

Expert opinion: Opioid receptors and ligands have been widely studied, and research into how different opioid subtypes affect behaviours related to addiction (reward, dysphoria, motivation) suggests that they are tractable targets as anti-relapse treatments. Regarding opioid ligands as novel ‘anti-relapse’ medication targets, research suggests that a ‘non-selective’ approach to targeting opioid receptors will be the most effective.     

The role of adenosine A1 receptors in the nucleus accumbens during morphine withdrawal

Opioids are effective analgaesic agents, but serious adverse effects such as tolerance and withdrawal contribute to opioid dependence and limit their use. Opioid withdrawal is a common occurrence in human opiate addicts that is not life-threatening. Studies have shown that the mesocorticolimbic system, especially the nucleus accumbens, is an important region in drug addiction and adenosine receptors play a modulatory role in the mechanism of action of drug dependence and withdrawal. The aim of this study was to investigate the effects of the selective A₁ receptor agonist CPA (N⁶-cyclopentyladenosine) on withdrawal symptoms, and the concentration of dopamine and noradrenaline in the nucleus accumbens and locomotor activity behaviour during naloxone-precipitated withdrawal in morphine-dependent rats. The local administration of CPA (1.5, 3.0, and 6.0 mmol/L bilateral 250 nL) into the nucleus accumbens decreased the Gellert–Holtzman withdrawal scale, and increased concentrations of dopamine and noradrenaline in the same region during naloxone-induced withdrawal. Our findings suggest that administration of the A₁ receptor agonist significantly decreased withdrawal behaviours and increased dopamine and noradrenaline concentrations in opioid withdrawal in a dose-dependent manner. These results demonstrate that adenosine receptors should be examined as a potential mechanism that could be exploited for the treatment of morphine withdrawal.     

多巴胺D_3受体选择性配体治疗药物依赖的新进展

药物依赖是一种以复吸为特征的慢性脑病,迄今为止尚缺乏有效的防复吸药物。随着药物依赖及复吸神经生物学机制的研究不断深入,发现了一些潜在的药物干预靶点。靶向多巴胺D3受体(DAD3R)防复吸药物研究受到了广泛关注,DAD3R选择性分布在啮齿类动物及人脑内与药物依赖相关的中脑边缘多巴胺系统,在药物依赖发生发展过程中发挥着重要作用。本文重点介绍DAD3R在药物依赖中的作用及选择性配体治疗药物依赖研究的进展。     

μ/δ阿片受体相互调节作用及药物发现与设计策略

阿片类镇痛药镇痛活性好,广泛用于临床。阿片受体主要分为3种亚型,即μ、δ、κ阿片受体。目前临床上使用的阿片类镇痛药大多为μ受体激动剂,但易引起成瘾性、呼吸抑制等副作用。δ受体激动剂镇痛活性较弱,但δ受体激动剂和拮抗剂均能调节μ受体激动剂的镇痛作用,同时参与成瘾性等副作用形成。因此,设计具有μ/δ双重功效的药物是新一代低毒副作用镇痛药的发展方向。该文综述了具有μ/δ双重功效药物的研究现状,为设计低毒副作用镇痛药物提供新思路。     

阿片受体激动剂的镇痛作用及其靶点通路研究进展

疼痛是一种复杂的生理现象,目前主要运用药物进行镇痛.阿片类受体激动剂类镇痛药受到了越来越多的关注,阿片受体及其与药物的作用机制研究取得了较大发展,近年来逐渐被用于临床治疗疼痛,但由于没有研究可以对其镇痛以及成瘾的机制进行明确地阐释,因此阿片受体激动剂在临床上没有得到广泛应用.探讨阿片类受体的结构特点和作用机制,并在此基础上开发结构全新或新作用机制的镇痛药物,是推动阿片类受体激动剂在临床上用于镇痛治疗的前提.综述阿片类受体激动剂在镇痛方面的应用及其信号通路,可以为今后高选择性镇痛药的研发及临床治疗提供思路.     

非阿片类药物改善阿片类药物致呼吸抑制研究进展

阿片类药物通过作用于阿片受体,激活与受体偶联的G蛋白和(或)β-抑制蛋白等信号通路而发挥镇痛和麻醉等效应,但同时阿片类药物致呼吸抑制(OIRD)则是临床常见的严重问题。目前通常采用阿片受体拮抗剂纳洛酮等改善OIRD,但纳洛酮可能会拮抗阿片类药物的镇痛作用,甚至带来许多不可预知的不良反应。近年来,使用非阿片类药物直接和(或)间接调节呼吸中枢,在改善OIRD的同时不影响阿片类药物的镇痛已成为一种新的研究思路。本文围绕近年来研究报道较多的α-氨基-3-羟基-5-甲基-4-恶唑丙酸受体调节剂、5-羟色胺受体激动剂、磷酸二酯酶4抑制剂、胶质细胞抑制剂、烟碱乙酰胆碱受体激动剂和钾离子通道阻滞剂等非阿片类药物展开综述。     

急性阿片处理对学习记忆功能的影响

阿片长期处理能够造成动物对阿片产生顽固性的病理性记忆,表明学习记忆参与了阿片依赖过程。阿片本身对动物的学习记忆过程也能产生明显的影响。基于不同的研究模型和不同的给药方案,阿片可能分别对记忆形成、巩固和再现过程表现出抑制或促进作用,其作用的复杂性反映了阿片受体及其与多种非阿片受体间相互作用的多样性。尽管目前仍有争论,但有关这方面的研究已经取得了较大进展。     

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

Opioids are widely used in the treatment of severe pain. The clinical use of the opioids is limited by serious side effects such as respiratory depression, constipation, development of tolerance, and physical dependence and addiction liabilities. Most of the currently available opioid analgesics exert their analgesic and adverse effects primarily through the opioid mu receptors. A large number of biochemical and pharmacological studies and studies using genetically modified animals have provided convincing evidence regarding the existence of modulatory interactions between opioid mu and delta receptors. Several studies indicate that delta receptor agonists as well as delta receptor antagonists can provide beneficial modulation to the pharmacological effects of mu agonists. For example, delta agonists can enhance the analgesic potency and efficacy of mu agonists, and delta antagonists can prevent or diminish the development of tolerance and physical dependence by mu agonists. On the basis of these observations, the development of new opioid ligands possessing mixed mu agonist/delta agonist profile and mixed mu agonist/delta antagonist profile has emerged as a promising new approach to analgesic drug development. A brief overview of mu-delta interactions and recent developments in identification of ligands possessing mixed mu agonist/delta agonist and mu agonist/delta antagonist activities is provided in this report.     

Distinct Mu,Delta, and Kappa Opioid Receptor Mechanisms Underlie Low Sociability and Depressive-Like Behaviors During Heroin Abstinence

Addiction is a chronic disorder involving recurring intoxication, withdrawal, and craving episodes. Escaping this vicious cycle requires maintenance of abstinence for extended periods of time and is a true challenge for addicted individuals. The emergence of depressive symptoms, including social withdrawal, is considered a main cause for relapse, but underlying mechanisms are poorly understood. Here we establish a mouse model of protracted abstinence to heroin, a major abused opiate, where both emotional and working memory deficits unfold. We show that delta and kappa opioid receptor (DOR and KOR, respectively) knockout mice develop either stronger or reduced emotional disruption during heroin abstinence, establishing DOR and KOR activities as protective and vulnerability factors, respectively, that regulate the severity of abstinence. Further, we found that chronic treatment with the antidepressant drug fluoxetine prevents emergence of low sociability, with no impact on the working memory deficit, implicating serotonergic mechanisms predominantly in emotional aspects of abstinence symptoms. Finally, targeting the main serotonergic brain structure, we show that gene knockout of mu opioid receptors (MORs) in the dorsal raphe nucleus (DRN) before heroin exposure abolishes the development of social withdrawal. This is the first result demonstrating that intermittent chronic MOR activation at the level of DRN represents an essential mechanism contributing to low sociability during protracted heroin abstinence. Altogether, our findings reveal crucial and distinct roles for all three opioid receptors in the development of emotional alterations that follow a history of heroin exposure and open the way towards understanding opioid system-mediated serotonin homeostasis in heroin abuse.