Exploring the Potential of Glia for Regulating Clinically Relevant Opiod Actions

探索神经胶质细胞调节临床相关阿片类药物作用的潜力

• 批准号: 8267435
• 负责人: LINDA WATKINS
• 金额: $ 1.19万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267435
• 关键词: Absence of pain sensation; Adverse effects; Affect; Analgesics; Asthma; Astrocytes; Ataxia; Behavior; Blood - brain barrier anatomy; Body Weight decreased; Brain; Brain region; Cataloging; Catalogs; Circadian Rhythms; Clinical; Clinical Trials; Commit; Complex; Data; Dependence; Development; Dizziness; Dose; Drug Kinetics; Drug usage; Employee Strikes; Experimental Designs; Exposure to; Goals; Grant; Human; Income; Intellectual Property; Investigation; Japan; Japanese Population; Knowledge; Laboratories; Left; Literature; Maintenance; Measures; Mediating; Messenger RNA; Microglia; Morphine; Morphine Dependence; Naloxone; Neuroglia; Neurons; Opiate Addiction; Opioid; Opioid Receptor; Pain; Pattern; Pentobarbital Sodium; Pharmaceutical Preparations; Phase; Physiological; Play; Principal Investigator; Private Sector; Proteins; Published Comment; Rattus; Regimen; Regulation; Relative (related person); Reporting; Research; Rewards; Role; Safety; Sedation procedure; Sleep; Spinal; Spinal Cord; Staging; Stimulus; Substance Withdrawal Syndrome; Surveys; Testing; Text; Time; United States; United States National Institutes of Health; Up-Regulation; Ventilatory Depression; Wages; Withdrawal; addiction; base; cell type; clinically relevant; cost; cytokine; drug craving; experience; high risk; in vivo; inhibitor/antagonist; milligram; neurochemistry; novel; opioid abuse; painful neuropathy; phrases; post stroke; pre-clinical; preclinical study; preference; prevent; programs; propentofylline; relating to nervous system; research study; response; statistics; success; volunteer

DESCRIPTION (provided by applicant): It has recently been discovered that glia become progressively more activated upon repeated exposure to morphine, & that this glial activation, in turn, modulates morphine's effects. This discovery was originally made in the context of studying the pain suppressive effects of morphine in spinal cord. The possibility that glia may be fundamentally important in determining the effects of opioids such as morphine is novel & important in its implications. Because of this, we propose to explore whether glia may profoundly alter the effects of repeated morphine in brain, as well. We believe that glia will prove to be powerfully involved in several phenomena currently thought to arise purely as a result of opioid effects on neurons; that is, dependence/withdrawal, reward & aversion. If this were true, it would provide evidence that glia are critically involved, not only in modulating the pain-suppressive effects of opioids, but also in key phenomena associated with human opioid abuse & addiction. Having considered the clinical importance of opioid dependence/withdrawal, reward & aversion & the paucity of knowledge regarding glial involvement in any of these, we have chosen to first determine the range of opioid-related phenomena in which glia & glial products play an important role, before detailed analyses of any single phenomenon. We chose this strategy as it is the right approach for this stage of investigation. The data to be obtained will provide guidance as to which of these phenomena should later be studied in detail, including issues of generality to other opioid & non-opioid drugs beyond morphine. The aims of the proposal are: (1) To define whether glial activation contributes to the development &/or maintenance of morphine dependence. This will be accomplished by characterizing whether inhibition of glial activation before or after establishment of opioid dependence impacts the expression of morphine withdrawal. Whether glia contribute to CNS side effects associated with dependence-inducing opioid administration will be assessed as well. (2) To characterize changes induced in glia by in vivo morphine dependence/withdrawal. Here, (a) brain regions implicated in the effects of repeated morphine & (b) rapidly isolated microglia will each be examined using immunohistochemical, protein &/or mRNA analyses. (3) To define whether glial activation contributes to morphine reward or aversion. This will be accomplished by characterizing whether inhibition of glial activation disrupts conditioned place preference &/or conditioned place aversion. In these studies, inhibition of glial activation will be accomplished in 2 ways: (a) using 2 blood-brain barrier permeable glial activation inhibitors & (b) blocking the recently discovered non-classical opioid receptor on glia. It has recently been discovered that glia become progressively more activated upon repeated exposure to morphine & that this glial activation, in turn, decreases the ability of morphine to suppress pain. This proposal extends the exploration of glial regulation of opioid actions, by examining whether glia are powerfully involved in several phenomena currently thought to arise purely as a result of opioid effects on neurons; that is, dependence/withdrawal, reward & aversion. If this proves true, it would provide evidence that glia are critically involved, not only in modulating the pain-suppressive effects of opioids, but also in key phenomena associated with human opioid abuse & addiction.

描述（由申请人提供）：最近发现，在反复接触吗啡时，胶质逐渐被激活，而这种神经胶质激活反过来又调节了吗啡的效果。该发现最初是在研究吗啡在脊髓中的疼痛抑制作用的背景下进行的。神经胶质在确定吗啡等阿片类药物的作用方面可能至关重要的可能性在其含义上是新颖而重要的。因此，我们建议探索神经胶质是否也可以深刻地改变大脑中重复吗啡的作用。我们认为，GLIA将被证明是有力地参与目前被认为是由于阿片类药物对神经元作用而产生的几种现象。也就是说，依赖/提取，奖励和厌恶。如果这是真的，它将提供证据表明神经胶质是关键参与的，不仅在调节阿片类药物的疼痛抑制作用方面，而且还与与人类阿片类药物滥用和成瘾有关的关键现象。在考虑了阿片类药物依赖性/戒断，奖励和厌恶以及有关神经胶质参与其中任何一个的知识的临床重要性之后，我们选择首先确定阿片类药物相关现象的范围，在详细分析任何单一现象之前，胶质和神经胶质产物起着重要作用，在这些现象中起着重要作用。我们选择了这种策略，因为它是调查阶段的正确方法。要获得的数据将提供有关以后应详细研究这些现象的指导，包括对吗啡以外的其他阿片类药物和非阿片类药物的通用性问题。该提案的目的是：（1）定义神经胶质激活是否有助于吗啡依赖性的发展和/或维持。这将通过表征在建立阿片类药物依赖之前或之后的抑制神经胶质激活是否会影响吗啡戒断的表达来实现。是否还会评估GLIA是否有助于与依赖性诱导阿片类药物相关的CNS副作用。 （2）表征通过体内吗啡依赖/戒断引起的神经胶质引起的变化。在这里，（a）使用免疫组织化学，蛋白质和/或mRNA分析来检查重复吗啡及其迅速分离的小胶质细胞的影响的大脑区域。 （3）定义神经胶质激活是否有助于吗啡奖励或厌恶。这将通过表征抑制神经胶质激活是否会破坏有条件的位置偏好和/或条件性位置厌恶来实现。在这些研究中，将通过两种方式来完成神经胶质激活的抑制：（a）使用2种血脑屏障渗透性神经胶质激活抑制剂；（b）阻止最近发现的胶质上的非经典阿片类药物受体。 最近发现，在反复接触吗啡时，神经胶质会逐渐被激活，而这种神经胶质激活又降低了吗啡抑制疼痛的能力。该提案通过研究神经胶质是否有力地参与目前被认为是由于阿片类对神经元的影响而纯粹参与的几种现象，从而扩展了对阿片类药物作用的神经胶质调节的探索。也就是说，依赖/提取，奖励和厌恶。如果证明是正确的，它将提供证据表明神经胶质是关键参与的，不仅在调节阿片类药物的疼痛抑制作用方面，而且还与与人类阿片类药物滥用和成瘾有关的关键现象。