与阿片类药物依赖相关的非阿片受体

药物依赖是药物长期与机体相互作用后引起的一种慢性复发性脑病,其本质是代偿性适应,有多种神经递质受体参与,包括阿片类受体和非阿片类受体,涉及复杂的神经生物学机制,迄今未被完全阐明。自从1973年人们确证体内存在阿片受体以来,国内外对阿片受体进行了大量的研究,明确了它是阿片类药物发挥奖赏的起始作用位点,长期在激动剂的作用下发生代偿性适应。但此后人们发现在药物依赖形成过程中的某些非阿片受体也发生代偿性变化,     

阿片类药物依赖对女性生殖内分泌系统及骨的影响

<正>近年来,由于阿片类药物的广泛应用,尤其是女性滥用阿片类药物人数的不断增加及此类药物在临床疼痛治疗中所占的重要地位,阿片类药物对机体各系统的损害已引起人     

甲基纳曲酮治疗阿片类药物引起的阿片性肠功能失调的研究进展

目的:为甲基纳曲酮治疗阿片类药物引起的阿片性肠功能失调提供参考。方法:对国内外甲基纳曲酮治疗阿片类药物引起的阿片性肠功能失调的研究进展作一综述。结果与结论:阿片类药物是治疗癌性疼痛的重要手段,但由于缓解疼痛的同时会对胃肠道产生直接作用而导致阿片性肠功能失调,严重影响其临床的广泛应用。甲基纳曲酮是一种选择性作用于阿片外周受体的拮抗药,能在不影响阿片中枢镇痛效应的同时阻断阿片性肠功能失调的发生。     

阿片类药物在豚鼠回肠上的依赖性

<正> 整体动物测定阿片类药物的身体依赖性耗药多、费时,因此有必要建立体外模型用于药物初筛。我们在豚鼠回肠上建立一个快速简便地测定阿片类药物依赖性的体外模型,并且应用此模型研究阿片受体亚型选择性配体的交叉依赖性。豚鼠回肠和阿片类药物在37℃孵育1-6 h后,拮抗剂纳洛酮可引起戒断性收缩。戒断性收缩的高度随孵育时间的延长而迅速增加,并且直接依赖于培养液中阿片类药物的浓度和催促的纳洛酮浓度。成瘾性较弱的药物如烯内吗啡、度冷丁和羟甲芬太尼的戒断性收缩明显弱于吗啡、芬太尼和υ50488H的戒断性收缩。     

阿片类药物调节机体免疫系统的研究进展

阿片类药物的持续摄入会严重影响机体免疫功能。吗啡和海洛因等滥用可破坏免疫系统,造成免疫功能紊乱,从而增加感染各种病原菌的几率和感染性疾病的发生率,同时诱发各种恶性并发症。然而,其导致免疫功能紊乱的机制仍不清楚。本文就阿片类药物依赖者免疫功能改变作简要综述,以阐述阿片类药物滥用对机体体液和细胞免疫的影响、对中枢神经系统免疫功能的改变及其通过干扰肠道微生态而对免疫系统造成的间接影响,为深入研究阿片类药物对机体免疫系统的调节机制提供理论基础。     

阿片类药物在豚鼠回肠上的依赖性

整体动物测定阿片类药物的身体依赖性耗药多、费时，因此有必要建立体外模型用于药物初筛。我们在豚鼠回肠上建立一个快速简便地测定阿片类药物依赖性的体外模型，并且应用此模型研究阿片受体亚型选择性配体的交叉依赖性。豚鼠回肠和阿片类药物在37℃孵育1-6b后，拮抗剂纳洛酮可引起戒断性收缩。     

阿片类药物成瘾者执行功能的研究进展

执行功能在阿片成瘾的形成、维持、戒治与复发中都具有重要作用。长期慢性的阿片类药物滥用会导致成瘾者的执行功能普遍受到损伤,继而影响药物成瘾的戒治与复发。本文梳理了近年来阿片类药物在神经心理学、事件相关电位以及影像学等领域的执行功能相关研究结果,以期为我国的阿片类药物成瘾的戒治工作提供来自认知神经科学的科学依据。     

防滥用阿片类镇痛药研究进展及专利分析

阿片类镇痛药是治疗中至重度疼痛的有效药物,但其潜在的成瘾性也使之成为常见的被滥用药物.随着阿片类药物使用的增加,滥用所导致的社会问题在全球范围内不断凸显.美国在阿片类药物防滥用制剂开发方面处于世界领先水平,为减少阿片类药物滥用,率先鼓励开发防滥用阿片类镇痛药.目前已开发了多种防滥用技术,包括形成物理/化学屏障、添加激动...     

阿片类药物的僵住作用及其受体调节机制

阿片类药物对运动功能产生的影响一直是人们十分感兴趣的问题。早在本世纪初人们就发现阿片类药物能使大鼠产生僵住症。给大鼠注射较高剂量的吗啡、美散痛、埃托啡、噻芬太尼和β-内啡肽等,可观察到明显的僵住症状。阿片类药物的僵住作用可被纳洛酮阻滞,DA 受体激动剂阿朴吗啡和DA 前体l-DOPA也能很好地逆转阿片类药物的这种作用。人们认为,阿片类药物对运动功能所产生的这种作用是与中枢多巴胺系统密切相关的。     

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…     

Opioids: old drugs for potential new applications

Opioids are commonly used analgesics in clinical practice. Three opioid receptors (mu, delta and kappa) that mediate opioid effects have been identified by molecular cloning. Each type of opioid receptors consists of subtypes of receptors as suggested by pharmacological studies. Although mu opioid receptors are the major receptor to mediate the analgesic effects of opioids, delta and kappa receptors are also important in anti-nociception (for example, delta and kappa receptors can mediate spinal analgesia). Recently, the cytoprotective effects of opioids have been recognized. The presence of opioids during harmful events such as ischemia reduces cell injury in multiple organs including heart and brain. These effects appear to be mediated by delta receptors in most studies. A new form of cytoprotection in which a prior exposure to opioids renders protection against cell ischemia (opioid preconditioning) has been identified. In the heart, this opioid preconditioning-induced protection has been well documented by multiple studies and may be mediated by delta receptors, G(i/o) proteins, protein kinase C, ATP-sensitive potassium channels and free radicals. Our initial study suggests that opioid preconditioning also induces neuroprotection. This neuroprotection involves delta(1) receptors, mitochondrial ATP-sensitive potassium channels and free radical production. In this review, we will briefly describe the analgesic effects of opioids. We will focus our discussion on opioid preconditioning-induced protection and its mechanisms. Opioids and agents that specifically work on the signaling molecules for opioid preconditioning-induced protection may prove to be useful in inducing protection against ischemia in clinical practice.     

肾功能不全癌症疼痛患者阿片类药物的应用

阿片类药物是控制癌症疼痛(简称癌痛)的重要药物,若品种及剂量使用不当,将会进一步造成肾脏损伤。癌症患者由于疾病本身或并发症的进展,可能会伴有肾功能不全。因此存在肾功能不全风险的癌痛患者,必须正确评估肾功能状态,结合疼痛程度和阿片类药物特性,正确选择药品品种和剂量。该文综述常用阿片类药物的药动学特征、肾功能不全患者和透析患者阿片类药物的选择等,以期为临床合理用药提供参考。     

CYP2D6 in the metabolism of opioids for mild to moderate pain

In most cancer patients, pain is successfully treated with pharmacological measures using opioid analgesics for moderate to severe pain (strong opioids) alone or in combination with adjuvant analgesics (coanalgesics). Opioids for mild to moderate pain (weak opioids) are usually recommended in the treatment of cancer pain of mild to moderate intensity. There is a debate whether the second step of the WHO analgesic ladder comprising weak opioids such as tramadol, codeine and dihydrocodeine is still needed for the treatment of cancer and chronic pain since low doses of strong opioids show similar efficacy. However, many patients with mild, moderate and in some cases strong pain intensity are still successfully treated with weak opioids. All these drugs are metabolized through CYP2D6, an important enzyme for approximately 25% of all drugs administered in clinical practice. The aim of this review is to summarize data on the impact of CYP2D6 polymorphism on pharmacokinetics, pharmacodynamics and adverse effects of weak opioids.     

The role of opioid analgesics in rheumatoid disease in the elderly population

Adequate pain therapy is an important aspect in the treatment of the elderly patient with rheumatoid disease. Problems with traditional NSAIDs include potentially serious gastrointestinal, cardiovascular and renal adverse effects, especially in the elderly. In addition, the selective cyclo-oxygenase-2 inhibitors have been associated with renal and cardiovascular adverse effects which may limit their use in the elderly with renal or cardiovascular disease. Opioids provide a treatment option for the management of pain in elderly patients with rheumatoid disease in whom pain control under standard management is poor; however, various therapeutic difficulties are encountered in the heterogeneous elderly population (increased risk of adverse effects, multimorbidity, and polypharmacy). Lower initial opioid dosage, prolonged dosage intervals and slower dosage titrations are advisable because of altered pharmacokinetics and pharmacodynamics. Kidney function should be tightly monitored and a timely use of laxatives is to be encouraged. Randomised clinical studies of opioids in musculoskeletal pain (e.g. osteoarthritis) have increasingly extended the scientific basis for their use. However, no randomised controlled clinical trials have examined the efficacy and the benefit/risk ratio of opioids in rheumatoid arthritis. Opioids also demonstrate an analgesic effect following local peripheral application. This opens the way to new therapeutic options in the future through the development of systemic peripherally selective opioids without CNS adverse effects.     

阿片类药物所致呼吸抑制与基因多态性

阿片类药物目前在临床上应用广泛,中度至重度疼痛以及大多数术后疼痛的治疗多依赖于阿片类药物的使用。目前临床上常用的吗啡等阿片类镇痛药治疗指数范围窄,个体差异较大,而且常常伴随着严重的耐受性和成瘾性,甚至呼吸抑制(RD)等严重不良反应。研究阿片受体的基因多态性有助于从分子生物学的角度解释个体间对阿片类药物反应存在的差异。确定基因特异性有助于指导临床用药,降低其呼吸抑制等不良反应的发生率。     

Opioids suppress chemokine-mediated migration of monkey neutrophils and monocytes - an instant response

Opioid users having acquired human immunodeficiency syndrome (AIDS) are at a greater risk than non-users of contracting opportunistic infections. Opioid-administered and simian immunodeficiency virus (SIV)-infected rhesus monkeys have been an excellent model for studying AIDS and drug abuse in humans. In this study, chemotaxis of monkey leukocytes was evaluated using the chemokines interleukin-8 (IL-8) and regulated upon activation, normal T cell expressed (RANTES) as the chemoattractants, and the effects of various opioid agonists and antagonists on the efficiency of chemotaxis were examined. Opioids were either incubated with monkey leukocytes or added directly to chemokines, and the number of cells migrating toward IL-8 (for neutrophils) or RANTES (for monocytes) was scored. Inhibition of chemotaxis was seen with both assay conditions, and the inhibition was mediated by opioids binding to mu or kappa receptors. Binding to delta opiod receptors was rarely, if ever, observed. Although opioids themselves may act as weak chemoattractants for monkey leukocytes, addition of opioid agonists to chemokines would reduce the chemoattractant ability of the chemokines. Opioids did not cause the same inhibitory effect on the chemotactic migration of neutrophils when the complement component C5a or the chemotactic peptide N-formyl-MET-LEU-PHE (fMLP) was used as chemoattractant. These studies suggest that the presence of opioids during SIV infection immediately alters chemokine-mediated immune functions.     

癌性疼痛药物不良反应的防治

治疗癌性疼痛最常用的的药物是阿片类药物和非甾体消炎药。阿片类药物常见的不良反应包括便秘、恶心、呕吐、呼吸抑制和尿潴留等。非甾体消炎药常见的不良反应包括胃肠道损伤、肝肾损伤、血液系统损害等。治疗时以预防不良反应为主,包括避免用于高危人群、控制剂量与时间、同时使用治疗不良反应的药物等。出现不良反应时应及时采取相应的治疗措施。     

The other side of the opioid story: modulation of cell growth and survival signaling

Opioids have been used as pain control medications for thousands of years. Opioids are highly effective analgesics clinically available for controlling moderate and severe pain. Recent genetic knockout and knockin studies have definitively demonstrated that the analgesic effect is mediated through opioid receptors. In addition to their analgesic effect, opioids also have the potential to develop tolerance and physical dependence. Moreover, opioids can modulate cell proliferation and survival. Attempts to design better opioid drugs to eliminate or diminish these undesirable effects for clinical benefits have achieved limited success. In recent years, investigation of the effects of opioid-mediated cell proliferation and survival has been very active, resulting in many publications. However, the molecular targets of such non-analgesic effects are complex. Several important pathways that control cell proliferation, survival, and apoptosis have been reported to be associated with the non-analgesic effects, which may be mediated through both opioid receptor signaling and other non-opioid receptor molecular entity-mediated signaling. This review tries to bring the attention of the medicinal chemistry community to new developments and advances in the research areas of opioid-mediated cell proliferation and survival. Further investigation of the molecular mechanism of these non-analgesic opioid effects may eventually yield useful information such as new drug targets, which may be explored to benefit for clinical treatments such as targeted cancer therapy, cancer pain management, regeneration of neurons, and recovery from drug addiction.     

Opioids as modulators of cell death and survival--unraveling mechanisms and revealing new indications

Opioids are powerful analgesics but also drugs of abuse. Because opioid addicts are susceptible to certain infections, opioids have been suspected to suppress the immune response. This was supported by the finding that various immune-competent cells express opioid receptors and undergo apoptosis when treated with opioid alkaloids. Recent evidence suggests that opioids may also effect neuronal survival and proliferation or migrating properties of tumor cells. A multitude of signaling pathways has been suggested to be involved in these extra-analgesic effects of opioids. Growth-promoting effects were found to be mediated through Akt and Erk signaling cascades. Death-promoting effects have been ascribed to inhibition of nuclear factor-kappaB, increase of Fas expression, p53 stabilization, cytokine and chemokine release, and activation of nitric oxide synthase, p38, and c-Jun-N-terminal kinase. Some of the observed effects were inhibited with opioid receptor antagonists or pertussis toxin; others were unaffected. It is still unclear whether these properties are mediated through typical opioid receptor activation and inhibitory G-protein-signaling. The present review tries to unravel controversial findings and provides a hypothesis that may help to integrate diverse results.     

阿片类药物不良反应的性别差异

阿片类药物是临床中广泛用于治疗中度至重度疼痛的药物。阿片类药物不良反应的性别差异近年日益受到重视,其中包括药物在呼吸抑制、胃肠道反应、心血管反应、镇痛耐受性及药物依赖性等方面的差异。进一步研究阿片类药物不良反应的性剐差异,将有助于更好地实施个体化用药。