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 This discovery was originally made in the context of studying the pain suppressive effects of morphine in spinal cord.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，神经胶质细胞在反复暴露于吗啡后变得逐渐更加激活，并且这种神经胶质细胞激活反过来调节吗啡的作用。这一发现最初是在研究吗啡对脊髓的疼痛抑制作用的背景下做出的。神经胶质细胞在确定吗啡等阿片类药物的作用方面可能具有根本性的重要作用，这一可能性是新颖且重要的。因此，我们建议探索神经胶质细胞是否也可能深刻改变重复吗啡对大脑的影响。我们相信，神经胶质细胞将被证明与目前认为纯粹是阿片类药物对神经元作用所致的几种现象密切相关。即依赖/退缩、奖励和厌恶。如果这是真的，它将提供证据表明神经胶质细胞不仅参与调节阿片类药物的镇痛作用，而且还参与与人类阿片类药物滥用和成瘾相关的关键现象。考虑到阿片类药物依赖/戒断、奖励和厌恶的临床重要性以及对神经胶质细胞参与其中任何一个的知识的缺乏，我们选择首先确定神经胶质细胞和神经胶质产物在其中发挥重要作用的阿片类药物相关现象的范围，然后再对任何单一现象进行详细分析。我们选择这种策略是因为它是现阶段调查的正确方法。获得的数据将为以后应详细研究哪些现象提供指导，包括吗啡以外的其他阿片类药物和非阿片类药物的普遍性问题。该提案的目的是：（1）确定神经胶质激活是否有助于吗啡依赖性的发展和/或维持。这将通过表征在阿片类药物依赖建立之前或之后抑制神经胶质活化是否影响吗啡戒断的表达来实现。神经胶质细胞是否会导致与阿片类药物依赖性诱导相关的中枢神经系统副作用也将被评估。 (2) 表征体内吗啡依赖/戒断引起的神经胶质细胞的变化。在这里，（a）与重复吗啡作用有关的大脑区域和（b）快速分离的小胶质细胞将分别使用免疫组织化学、蛋白质和/或 mRNA 分析进行检查。 (3) 确定神经胶质细胞激活是否有助于吗啡奖赏或厌恶。这将通过表征神经胶质激活的抑制是否破坏条件性位置偏好和/或条件性位置厌恶来实现。在这些研究中，神经胶质细胞活化的抑制将通过两种方式实现：（a）使用2种血脑屏障可渗透的神经胶质细胞活化抑制剂；（b）阻断最近发现的神经胶质细胞上的非经典阿片受体。 最近发现，反复接触吗啡后，神经胶质细胞会逐渐变得更加激活，而这种神经胶质细胞的激活反过来会降低吗啡抑制疼痛的能力。该提案通过检查神经胶质细胞是否有力地参与了目前认为纯粹是由于阿片类药物对神经元的作用而产生的几种现象，扩展了神经胶质细胞对阿片类药物作用的调节的探索；即依赖/退缩、奖励和厌恶。如果这一点被证明是正确的，它将提供证据表明神经胶质细胞不仅在调节阿片类药物的镇痛作用中发挥着重要作用，而且在与人类阿片类药物滥用和成瘾相关的关键现象中也发挥着重要作用。