阿片受体的耐受机制

阿片类药物是临床疼痛治疗中重要的选择药物,限制其长期使用的主要原因在于患者生理耐受性和药物依赖性的发生。多种给药途径、不同剂量(从超低到高剂量)以及给药时间(如间歇性或持续)均可造成阿片类药物的耐受。阿片类药物的使用是一把双刃剑。它们最初被用于镇痛和抗痛觉过敏,但随后的实验研究和临床观察发现,长期使用阿片类药物会导致急性阿片类耐受(acute opioid tolerance,AOT)和阿片类诱导的痛觉过敏(opioid-induced hyperalgesia, OIH)。有研究表明,阿片类药物即使在临床接受的剂量范围内使用,也会引起剂量或时间依赖性的急性耐受性和痛觉过敏。要在实现临床疗效的情况下同时减轻或有效阻止阿片耐受的形成是一个亟待解决的问题。因此,本文主要简述了阿片受体中最重要的μ阿片受体耐受的形成机制,以期为阿片耐受的治疗提供理论依据。     

成瘾行为的表观遗传调节与治疗的研究进展

药物成瘾戒断后的复吸是一个世界性的重大医学难题,目前国内外采用的脱毒治疗方法虽然可以帮助成瘾患者暂时摆脱毒品,但无法阻止戒断后的高复吸现象。因此,研究复吸的神经机制并研发有效的干预方法成为治疗药物成瘾的关键。近年来,大量研究表明成瘾药物的使用会引起神经系统的表观遗传修饰发生改变,由于表观遗传对基因表达的调节作用具有持久性,所以在一定程度上可以解释成瘾行为长期性的原因。此外,人为调控表观遗传机制能够持久性的影响成瘾相关基因的表达,进而调节成瘾行为,所以表观遗传学的发展为探索药物成瘾与复吸的机制以及治疗方法提供了新的思路。表观遗传对基因表达调节的机制主要包括组蛋白的修饰、DNA的甲基化以及非编码RNA的表达。本文综述了近年来通过调控表观遗传机制来影响成瘾行为、尤其是干预复吸行为的最新研究进展,讨论了表观遗传治疗药物成瘾的思路,以期为临床上通过表观遗传治疗药物成瘾及预防复吸提供理论参考。     

两种复吸动物模型的神经生物学机制

复吸是指撤药一段时间后,觅药和用药行为的恢复。它是药物成瘾的主要特征之一,也是药物成瘾治疗亟待解决的头号难题。本文介绍两种复吸动物模型——自身给药消退恢复模型、条件性位置偏爱消退复燃模型建立的方法,对模型的效标效度进行评价,探讨复吸的神经生物学机制,为药物成瘾的治疗提供研究思路。     

军事医学研究院神经精神药理学研究进展

神经精神药理学是药理学的重要组成部分,主要任务是在研究神经精神疾病病理生理学机制的基础上,发现新的候选靶标和治疗药物.近年来,军事医学科学院在神经精神药理学研究领域开展了大量的研究工作,在一些主要研究方向的基础和应用研究领域,如镇痛、脱毒、防复吸、抗抑郁、抗焦虑、抗阿尔茨海默病、抗帕金森氏病、抗晕动病、抗疲劳等取得了许多重要的研究进展.本文就军事医学科学院药理学工作者在神经精神药理学研究领域的主要发现做一综述.     

GABA受体与药物依赖性的研究进展

药物成瘾是一种全球性的公共卫生问题,其发生机制十分复杂。γ-氨基丁酸(γ-aminobutyric acid,GABA)是中枢神经系统中主要的抑制性神经递质,其通过调节GABA受体(如:GABA_A,GABA_B)的活性参与多种药物成瘾和依赖性的发生与发展过程。吗啡、可卡因、甲基苯丙胺等药物引起的奖赏、戒断和复吸作用与GABA受体的激活或抑制密切相关。本文将对GABA受体在药物依赖中的作用及机制进行综述,从而为治疗药物成瘾提供新的策略。     

中央杏仁核神经元ERK-MAPK信号通路介导大鼠可卡因寻求行为

环境暗示诱发性可卡因戒断后复吸是一个重要的临床问题,最近美国国立卫生研究院的研究人员Yavin Shaham等利用大鼠渴求与复吸行为模型以及分子生物学方法,揭示了其中可能存在的中枢机制。研究发现,大鼠在可卡因戒断后第一个月内,其“环境暗示诱发性可卡因寻求行为”(cue-induced cocaine seeking)可呈时间依赖性增强。此现象提示,这段时间可能是药物渴求行为的重要形成期与增强期。     

阿片成瘾机制研究进展及治疗展望

关于阿片类药物成瘾机制的研究是药物成瘾研究中的一个热点,本文从参与阿片成瘾的神经递质系统及其相互作用、不同阿片受体在成瘾过程中的作用、学习记忆与阿片成瘾的关系、成瘾性药物的细胞内信号转导机制等几个方面介绍了近年来的研究进展,并对阿片类药物成瘾治疗和预防和新方法进行了展望。     

阿片类药物的耐受性和依赖性

近年来,不少学者从行为水平、器官水平、细胞和分子水平等不同层次深入探讨阿片类药物耐受性和依赖性的机理,试图搞清阿片受体和耐受性、依赖性的内在关系。一、耐受性和依赖性研究方法(一)整体实验测定药物依赖性的常用方法有小鼠跳跃、大鼠体重减轻、猴依赖吗啡、     

药物成瘾中不同环境线索诱发觅药行为的机制

接触药物相关环境线索可激发成瘾者对药物的渴求感及复吸行为。实验动物研究中药物相关环境线索分为三类:伴药线索、辨别线索和情境线索。在长期停药及用药行为消退后三种环境线索均能诱发觅药行为恢复,而行为机制各具特点:伴药线索条件性强化觅药行为,辨别线索直接激发觅药行为发生,情境线索设定场景诱发觅药行为恢复。三种线索行为效应的神经基础局部相同而又各具特点,其机制的研究有助于对成瘾药物复吸机制的理解及临床戒毒治疗。     

282例海洛因依赖者复吸原因调查分析

目的探讨海洛因依赖者复吸原因,并分析社会因素、心理因素和戒毒后稽延症状对复吸的影响。方法采用在北京大学中国药物依赖研究所编制的16项复吸原因问卷,调查282例海洛因依赖者吸毒、脱毒后复吸情况以及影响复吸的三方面因素。结果出现稽延性戒断症状（81．9％）、失眠（75．5％）是产生复吸的主要身体因素;消除心情烦恼（39．0％）、打发无聊时间（34．4％）以及再享受最后一次（32．6％）是产生复吸的主要心理因素;毒友影响（43．3％）、旧的吸毒环境又引发毒瘾（33．7％）是产生复吸的主要社会因素。讨论吸毒者的心理康复是预防复吸最重要工作的之一;加强对戒毒后回归社会人员的管理,建立家庭社区综合康复机制,是预防复吸的重要手段;加大在广大青少年人群中禁毒的宣传力度。     

Reinforcement processes in opiate addiction: A homeostatic model

The development of tolerance and dependence has traditionally been considered an integral aspect of the drug addiction process, and opiate dependence has been studied extensively as a model system in this regard. However, recent emphasis on the positive reinforcing properties of drugs has led to the suggestion that tolerance, dependence, and withdrawal may be of secondary or even negligible importance in motivating compulsive drug use. The current article argues for an integrated view of addiction in the form of a homeostatic neuroadaptation model which emphasizes the motivational significance of both the positive affective state produced by opiates and the negative affective state characteristic of drug withdrawal. The model is supported by evidence at both the behavioral and neural systems levels of analysis. Understanding the important distinction between somatic and affective components of opiate withdrawal is key to recognizing the factors which contribute to the motivational significance of opiate dependence and withdrawal. In addition, the critical role of conditioning processes in the maintenance of compulsive drug use and relapse after periods of abstention is discussed. Finally, it is argued that both the positive reinforcement produced by acute administration of a drug and the negative affective state produced by withdrawal are common to multiple classes of abused drugs, suggesting that an understanding of homeostatic neuroadaptation within motivational systems provides a key to the etiology, treatment and prevention of drug addiction. Special issue dedicated to Dr. Eric J. Simon.     

Drugs of abuse--opiates.

Treating opiate-dependent patients can be difficult for many physicians because the patients'' life-styles, values, and beliefs differ from those of the physicians. Primary care physicians, however, are often involved in the treatment of the medical complications of opiate abuse, and physicians must often manage a patient''s opiate dependence until appropriate referral to a drug abuse treatment program can be arranged. Treatment is guided by an understanding of the patient''s addictive disease, for which there are specific diagnostic criteria, and an understanding of the pharmacology of opiates of abuse and the medications used in treating opiate dependence. The opiate agonist, methadone, is useful for both detoxification and maintenance. The opiate antagonist, naloxone, is the treatment of choice for opiate overdose, and naltrexone, also an opiate antagonist, is a useful adjunct in subgroups of opiate-dependent patients for preventing relapse. New medications for the treatment of opiate dependence are being developed.     

Opiate tolerance and dependence: recent findings and synthesis.

Recent studies have led to a greater understanding of the behavioral, cellular, and molecular mechanisms underlying opiate tolerance and physical dependence. Behavioral studies have demonstrated that both direct pharmacological effects and the learning of interactions between drug effects and environmental cues are important in these phenomena. Behavioral studies have also revealed that N-methyl-D-aspartate receptors may play a role in their development (or acquisition). Although in early cellular studies no consistent role was found for opioid receptors or endogenous opioid peptides in opiate tolerance and dependence, recent experiments suggest that beta-endorphin, enkephalin, and dynorphin neurons may indeed have a role. Finally, studies at the molecular level suggest that a functional decoupling of opioid receptors from GTP-binding proteins (G proteins) may be important. In this review, we discuss these disparate findings and present a synthesis that shows how they might together contribute to the phenomena of opiate tolerance and physical dependence.     

What happens to opiate addicts immediately after treatment: a prospective follow up study.

In the first British study to investigate systematically what happens to opiate addicts after treatment 50 opiate addicts admitted for inpatient treatment of their drug dependence were followed up for six months after discharge. All had been withdrawn from opiates before follow up. Six months later 26 were not using opiates: 12 had not used opiates at any time since discharge. When subjects in hospital or in prison were excluded from the analysis 21 (47%) of the subjects living in the community were not taking opiates. Many subjects used opiates within days of leaving the inpatient unit, but this first lapse did not necessarily lead to a full relapse into addictive use. During the six months after discharge several subjects used opiates on a less than daily basis. During each two month period throughout the six months of follow up the proportion of subjects who were occasional users fell, the proportion of abstinent subjects grew, and the proportion of daily users (assumed to be readdicted) remained constant. Although many of the addicts relapsed soon after treatment, it was encouraging that almost half were opiate free after six months. These results have important implications for the treatment of drug addicts.     

Dependence creating properties of lipotropin C-fragment (beta-endorphin): evidence for its internal control of behavior

The C-fragment of lipotropin (β-endorphin) possesses reinforcing properties, in that this peptide, like heroin, induced intraventricular self-administering behavior in drug naive rats. Only mild behavioral signs reminiscent of physical dependence were present. After injection into the nucleus raphé magnus, C-Fragment appeared to act as a discriminative stimulus in rats trained to discriminate fentanyl from saline. These data indicate that naturally occuring C-Fragment exerts powerful control of behavior, which may be of significance for the understanding of the mechanisms underlying opiate dependence.     

Regulated endocytosis of opioid receptors: cellular mechanisms and proposed roles in physiological adaptation to opiate drugs

Opiate drugs such as morphine and heroin are among the most effective analgesics known. Prolonged or repeated administration of opiates produces adaptive changes in the nervous system that lead to reduced drug potency or efficacy (tolerance), as well as physiological withdrawal symptoms and behavioral manifestations such as craving when drug use is terminated (dependence). These adaptations limit the therapeutic utility of opiate drugs, particularly in the treatment of chronically painful conditions, and are thought to contribute to the highly addictive nature of opiates. For many years it has been proposed that physiological tolerance to opiate drugs is associated with a modification of the number or functional activity of opioid receptors in specific neurons. We now understand certain mechanisms of opioid receptor desensitization and endocytosis in considerable detail. However, the functional roles that these mechanisms play in the complex physiological adaptation of the intact nervous system to opiates are only beginning to be explored.     

Can the Chronic Administration of the Combination of Buprenorphine and Naloxone Block Dopaminergic Activity Causing Anti-reward and Relapse Potential?

Opiate addiction is associated with many adverse health and social harms, fatal overdose, infectious disease transmission, elevated health care costs, public disorder, and crime. Although community-based addiction treatment programs continue to reduce the harms of opiate addiction with narcotic substitution therapy such as methadone maintenance, there remains a need to find a substance that not only blocks opiate-type receptors (mu, delta, etc.) but also provides agonistic activity; hence, the impetus arose for the development of a combination of narcotic antagonism and mu receptor agonist therapy. After three decades of extensive research, the federal Drug Abuse Treatment Act 2000 (DATA) opened a window of opportunity for patients with addiction disorders by providing increased access to options for treatment. DATA allows physicians who complete a brief specialty-training course to become certified to prescribe buprenorphine and buprenorphine/naloxone (Subutex, Suboxone) for treatment of patients with opioid dependence. Clinical studies indicate that buprenorphine maintenance is as effective as methadone maintenance in retaining patients in substance abuse treatment and in reducing illicit opioid use. With that stated, we must consider the long-term benefits or potential toxicity attributed to Subutex or Suboxone. We describe a mechanism whereby chronic blockade of opiate receptors, in spite of only partial opiate agonist action, may ultimately block dopaminergic activity causing anti-reward and relapse potential. While the direct comparison is not as yet available, toxicity to buprenorphine can be found in the scientific literature. In considering our cautionary note in this commentary, we are cognizant that, to date, this is what we have available, and until such a time when the real magic bullet is discovered, we will have to endure. However, more than anything else this commentary should at least encourage the development of thoughtful new strategies to target the specific brain regions responsible for relapse prevention.     

戒毒药物新进展

目前戒毒药物的作用靶点主要包括阿片受体、M受体、a2受体、DA2受体、NMDA受体以及钙离子通道等,与此相对应的戒毒药物均具有较好的疗效,但长期使用会形成心理、躯体依赖及耐受性,停用时出现明显的戒断症状。中药戒毒有较好的发展前途,尤其在控制稽延症状方面优于西药阿片受体类及非阿片受体类。查阅近年来国内外公开发表的有关文章,按戒毒药物的性质分类汇总,并对近年来戒毒药物的研究进展作以综述。     

Cyclosporine alters opiate withdrawal in rodents

Opiates exert numerous effects on all levels of the central nervous system with tolerance, physical dependence and withdrawal being characteristics of this drug class. The degree of dependence is directly correlated to the intensity of withdrawal. Therefore, success in modifying the withdrawal syndrome may shed light on the dynamics of opiate addiction. The present study demonstrates that cyclosporine, a widely used immunosuppressive drug, considerably modified the behavioral signs of a naloxone-induced abstinence syndrome in morphine-addicted rats. In previous experiments, alpha-interferon has shown similar results. The similarity in actions of these two immunomodulator drugs is discussed and we suggest that opiate addiction may involve the immune system.     

A role for brain stress systems in addiction

Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take drugs and has been linked to dysregulation of brain regions that mediate reward and stress. Activation of brain stress systems is hypothesized to be key to the negative emotional state produced by dependence that drives drug seeking through negative reinforcement mechanisms. This review explores the role of brain stress systems (corticotropin-releasing factor, norepinephrine, orexin [hypocretin], vasopressin, dynorphin) and brain antistress systems (neuropeptide Y, nociceptin [orphanin FQ]) in drug dependence, with emphasis on the neuropharmacological function of extrahypothalamic systems in the extended amygdala. The brain stress and antistress systems may play a key role in the transition to and maintenance of drug dependence once initiated. Understanding the role of brain stress and antistress systems in addiction provides novel targets for treatment and prevention of addiction and insights into the organization and function of basic brain emotional circuitry.