镇痛药:阿片类及阿片受体

强有力的研究力量继续集中于探索内源性阿片类物质及其生物合成和代谢、多种阿片受体亚型以及开发特异性阿片受体配体等方面的研究。1982年对内源性阿片类物质与阿片受体,内啡肽与痛调节,阿片与非阿片类镇痛药,痛传递的神经机制,内啡肽的行为药理学,神经肽的中枢作用,内啡肽与脑啡肽以及应激(stress)与内源性阿片类物质均进行了综述。     

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…     

阿片受体固有活性与阿片类物质依赖

阿片类物质依赖作用的机理仍不完全清楚，近年来学术界对阿片受体固有活性与阿片类物质作用的关系表现出很大的兴趣。阿片受体慢性暴露于阿片类物质后固有活性的变化与阿片类物质依赖产生的关系是研究阿片类成瘾机制热点问题之一。     

阿片类药物依赖性的分子机制

对阿片类药物依赖性机理的研究，在行为、神经生化、细胞、分子水平上都有所进展。７０年代初证实了脑内有阿片受体，这成为研究阿片类依赖性机理的起点。人们试图用阿片受体数目或亲和力的变化或受体活性状态的转变来解释阿片类药物的耐受和依赖。然而，经过多年的研究，...     

美沙酮维持治疗存在的问题和应对的思考

美沙酮是阿片受体激动剂，第二次世界大战时由德国化学家合成。1960年，在美国研究发现该药能控制海洛因的戒断症状，与其他阿片类产生交叉依赖性和耐受性，可替代任何一种阿片类药物，开始用于戒毒治疗。近30年来，成为欧美等西方国家的主要戒毒药物。美沙酮维持治疗（Methadone Maintenance Treatment，MMT）是阿片类依赖人员口服美沙酮，     

非靶受体在精神活性物质依赖中的作用

当前精神活性物质滥用和成瘾呈上升趋势,它既是一个严重的社会问题,又是一个非常重要的生物学问题。在我国导致精神依赖的活性物质主要是阿片类。精神活性物质作用的靶受体为阿片受体,非靶受体主要包括多巴胺受体、N-甲基-D-门冬氨酸(NMDA)受体和组胺等。本文主要论述NMDA受体和组胺受体等非靶受体在精神活性物质依赖发生发展过程中功能和结构上的变化,探讨精神活性药物成瘾的机制,研究和开发以NMDA和组胺受体为靶标的新药,为阿片类药物成瘾的防治开辟新的研究领域。     

丁丙诺啡身体依赖性潜力评价:人体催促戒断反应

丁丙诺啡身体依赖性潜力评价：人体催促戒断反应丁丙诺啡是一个μ阿片受体的部分激动剂，临床上已证实可治疗阿片类依赖。与完全的阿片受体激动剂相比，丁丙诺啡的身体依赖性潜力较低。本研究使用阿片受体拮抗剂药物催促法，对临床常用维持剂量的丁丙诺啡产生的身体依赖性...     

硫酸镁用于PCA镇痛作用和疗效的观察

手术后的疼痛是引起患者对手术恐惧的一个重要原因,阿片类药物是缓解疼痛的基本用药。但是所有的阿片类药物都会产生副作用,如恶心、呕吐、瘙痒、呼吸抑制、便秘、耐药性和依赖性等情况,这就使患者担心出现这些副作用尤其是耐药性和依赖性而宁愿忍受痛苦也不愿意使用阿片类药物进行术后的疼痛治疗,如何有效地降低阿片药物的剂量是我们应该考虑的问题。镁作为一种天然生理性钙通道阻滞药和非竞争性的N-甲基-D-天冬氨酸(NMDA)谷氨酸受体拮抗剂,在疼痛和术后疼痛的调节中可能发挥重要作用。镁可以对NMDA受体及与其相关的离子通道发挥拮抗剂…     

κ阿片受体中枢副作用评价方法和发生机制研究进展

κ阿片受体激动会产生较强的镇痛作用,但不会诱发经典阿片样副作用,同时还可以拮抗阿片类物质成瘾。但由于其中枢镇静、烦躁不安副作用的存在,目前临床以κ阿片受体为靶标的药物多为κ/μ混合激动剂,尚缺乏选择性κ受体激动剂。开发中枢副作用小的κ受体激动剂将是新型镇痛药物的重要研究方向。该文对目前临床使用的以κ阿片受体为靶标的镇痛药、κ受体中枢副作用评价方法和发生机制进行综述。     

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。     

A cell biologist's perspective on physiological adaptation to opiate drugs

Opiate drugs such as morphine and heroin are among the most effective analgesics known but are also highly addictive. The clinical utility of opiates is limited by adaptive changes in the nervous system occurring after prolonged or repeated drug administration. These adaptations are believed to play an important role in the development of physiological tolerance and dependence to opiates, and to contribute to additional changes underlying the complex neurobehavioral syndrome of drug addiction. All of these adaptive changes are initiated by the binding of opiate drugs to a subfamily of G protein-coupled receptors that are also activated by endogenously produced opioid neuropeptides. It is increasingly evident that opiate-induced adaptations occur at multiple levels in the nervous system, beginning with regulation of opioid receptors themselves and extending to a complex network of direct and indirect modifications of "downstream" signaling machinery. Efforts in my laboratory are directed at understanding the biochemical and cell biological basis of opiate adaptations. So far, we have focused primarily on adaptations occurring at the level of opioid receptors themselves. These studies have contributed to defining a set of membrane trafficking mechanisms by which the number and functional activity of opioid receptors are controlled. The role of these mechanisms in affecting adaptation of "downstream" neurobiological substrates, and in mediating opiate-induced changes in whole-animal physiology and behavior, are exciting questions that are only beginning to be explored.     

Zipeprol is a newly abused antitussive with an opioid spectrum and hallucinogenic effects

Zipeprol is a non-opioid cough suppressor agent recently abused in Italy. Clinical reports from 30 street abusers show that the drug in high doses has a definite abuse liability and dependence potential. Many of its effects were identical to those induced by opiates, although specific dysperceptive symptoms were commonly reported by patients. Spontaneous withdrawal symptoms were similar to those of opiates. Withdrawal could be also precipitated by naloxone. It is concluded that zipeprol can induce dependence with a mechanism which may be mediated by some types of opioid receptors.     

双向阿片功能调节剂：胍丁胺

近年研究表明某些药物尽管不能与阿片受体发生相互作用，但能对阿片药理作用产生重要的调节．特别是有些药物能对阿片功能产生双向调节作用，即增强阿片镇痛，对抗阿片耐受和躯体依赖．我们将这些不与阿片受体发生作用，但具有双向调节阿片功能的药物称之为双向阿片功能调节剂(biphasic opioid function modulator，BOFM)．基于我们的研究工作，可以认定胍丁胺就是一个典型的双向阿片功能调节剂．胍丁胺本身有弱的镇痛作用，它能增强吗啡镇痛，对抗吗啡耐受和依赖：胍丁胺产生上述作用的主要机制与抑制阿片长期作用下在阿片受体信号转导系统产生的代偿性适应过程相关．     

A biphasic opioid function modulator: agmatine

Recently it has been revealed that some agents that are not able to interact with opioid receptors play an important role in regulating the pharmacological actions of opioids. Especially, some of them show biphasic modulation on opioid functions, which enhance opioid analgesia, but inhibit tolerance to and substance dependence on opioids. We would like to call these agents which do not interact with opioid receptors, but do have biphasic modulation on opioid functions as biphasic opioid function modulator (BOFM). Mainly based on our results, agmatine is a typical BOFM. Agmatine itself was a weak analgesic which enhanced analgesic action of morphine and inhibited tolerance to and dependence on opioid. The main mechanisms of agmatine were related to inhibition of the adaptation of opioid receptor signal transduction induced by chronic treatment of opioid.     

Involvement of neuropeptide FF receptors in neuroadaptive responses to acute and chronic opiate treatments

BACKGROUND AND PURPOSE Opiates remain the most effective compounds for alleviating severe pain across a wide range of conditions. However, their use is associated with significant side effects. Neuropeptide FF (NPFF) receptors have been implicated in several opiate-induced neuroadaptive changes including the development of tolerance. In this study, we investigated the consequences of NPFF receptor blockade on acute and chronic stimulation of opioid receptors in mice by using RF9, a potent and selective antagonist of NPFF receptors that can be administered systemically. EXPERIMENTAL APPROACH The effects of RF9 were investigated on opioid pharmacological responses including locomotor activity, antinociception, opioid-induced hyperalgesia, rewarding properties and physical dependence. KEY RESULTS RF9 had no effect on morphine-induced horizontal hyperlocomotion and slightly attenuated the decrease induced in vertical activity. Furthermore, RF9 dose-dependently blocked the long-lasting hyperalgesia produced by either acute fentanyl or chronic morphine administration. RF9 also potentiated opiate early analgesic effects and prevented the development of morphine tolerance. Finally, RF9 increased morphine-induced conditioned place preference without producing any rewarding effect by itself and decreased naltrexone-precipitated withdrawal syndrome following chronic morphine treatment. CONCLUSION AND IMPLICATIONS The NPFF system is involved in the development of two major undesirable effects: tolerance and dependence, which are clinically associated with prolonged exposure to opiates. Our findings suggest that NPFF receptors are interesting therapeutic targets to improve the analgesic efficacy of opiates by limiting the development of tolerance, and for the treatment of opioid dependence.     

Molecular basis of opioid dependence: role of signal regulation by G-proteins

1. Morphine and opiate narcotics are potent analgesics that have a high propensity to induce tolerance and physical dependence following their repeated administration. 2. The molecular basis of opiate dependence has not been completely elucidated, although the participation of opioid receptors is a prerequisite. Cellular dependence on opioids is believed to result from the chronic stimulation of opioid-regulated signalling networks. 3. As G-protein-coupled receptors, the opioid receptors must rely on heterotrimeric G-proteins for signal transduction. Recent advances in our understanding of G-protein signalling have unveiled novel signalling molecules and mechanisms, some of which may be intricately involved in the manifestation of opiate dependence. 4. In the present review, we will attempt to trace chronic opioid signals along elaborate G-protein-regulated pathways.     

Experimental Models of Opiate Tolerance and Dependence

Abstract: Since observations in whole animals provide only limited information on the mechanisms underlying tolerance and dependence, less complex isolated tissue, cell culture and single neurone models have been developed, the most widely exploited of which is the guinea pig ileum. Prolonged exposure to morphine leads to tolerance to its acute inhibitory effects. Dependence is indicated by neuronal hyperexcitability when morphine is withdrawn or abruptly displaced from its receptor by naloxone. The mechanism of withdrawal hyperexcitability may be relatively non-selective since responses of both central and peripheral neurones to a variety of excitants are enhanced. Behavioural and biochemical experiments implicate elevated neuronal calcium and adenylate cyclase in the expression of dependence. However the relationship between these observations and the hyperexcitability of single neurones has not been rigorously examined. Moreover the relevance of an analysis of tolerance and physical dependence in experimental models to opioid reward mechanisms is uncertain. Although recent evidence suggests the importance of the ventral tegmental area in the rewarding actions of opiates, the biochemical and electrophysiological effects of exogenous opiates and of endogenous opioids on these neurones remain largely unexplored.     

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。     

Antagonism by chlornaltrexamine of some effects of delta 9-tetrahydrocannabinol in rats

Chlornaltrexamine (beta-CNA) a selective, long-acting irreversible opiate antagonist inhibited the analgesia, hypothermia, hypothermia tolerance and physical dependence produced by delta 9-tetrahydrocannabinol (THC) in rats. The results suggest that there are some common features between cannabis and opiates and some actions of THC may be mediated by opioid related mechanisms in the central nervous system.