Microglial Regulation in Opioid Tolerance, Hyperalgesia and Addiction

小胶质细胞对阿片类药物耐受、痛觉过敏和成瘾的调节

• 批准号: 7691350
• 负责人: Joyce A De Leo
• 金额: $ 23.99万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7691350
• 关键词: Adult; Adverse effects; Analgesics; Astrocytes; Attenuated; Biological Assay; CCL2 gene; Cells; Chronic; Data; Development; Disease; Dose; Drug Addiction; Exposure to; Fentanyl; Glutamates; Hyperalgesia; ITGAM gene; Immigration; Immunofluorescence Immunologic; Immunohistochemistry; In Vitro; Injury; Investigation; Maintenance; Mediating; Memory; Messenger RNA; Methadone; Microglia; Monocyte Chemoattractant Protein-1; Morphine; Neonatal; Nervous system structure; Neuraxis; Neuroglia; Neurons; Nociception; Opioid; Opioid Receptor; Oxycodone; Pathology; Pharmaceutical Preparations; Pharmacopoeias; Physiologic pulse; Physiological; Posterior Horn Cells; Purinoceptor; Rattus; Receptor Activation; Regulation; Relapse; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Spinal; Stress; Surface; Time; Western Blotting; Xenobiotics; addiction; chemokine; chronic pain; craving; dorsal horn; drug discovery; drug of abuse; extracellular; in vivo; inhibitor/antagonist; intercellular communication; interdisciplinary approach; migration; monocyte chemoattractant protein 1 receptor; nerve injury; novel; painful neuropathy; patient population; protein expression; public health relevance; receptor; receptor expression; response; stressor; transmission process

DESCRIPTION (provided by applicant): The primary purpose of this proposal is to identify the effects of drugs of abuse (i.e. opioids) on glial cell mechanisms that contribute to drug-induced hyperalgesia and tolerance. These studies may also aid in elucidating substance abuse-induced plasticity, the physiological correlate to craving and relapse in drug addiction. Once thought to only serve a supportive role in the CNS, glial cells (specifically microglia and astrocytes) are now coming under intense investigation as major contributors to the pathology of many disorders including neuropathic pain, opioid tolerance and most recently, drug addiction. Following stress to the CNS (e.g. injury or xenobiotic administration) microglia become reactive as defined by enhanced surface or cytosolic protein expression, morphological changes, proliferation and migration. It has been proposed that once activated, specific microglia remain as postactivated or primed, i.e. they retain a memory to alter responses to subsequent stimulation. This could be an underlying mechanism for opioid tolerance following chronic administration, as well as drug addiction. We propose to study the role of microglia in opioid tolerance through investigation of the following hypothesis: Chronic opioids induce sustained CNS microglial reactivity leading to direct signaling between microglia and nociceptive neurons which manifests as hyperalgesia and/or tolerance. Further, we hypothesize that this selective activation potentiates extracellular ATP/ADP activation of P2X4 receptors initiating microglial migration. These migrating cells produce locally elevated chemokines (i.e. Monocyte Chemoattractant Protein-1/CCL2) and other diffusible proinflammatory factors, inducing dorsal horn neuron sensitization and tolerance formation. The overall hypothesis will be investigated using in vitro primary neonatal cortical and adult spinal microglia, in vivo adult rats and through the completion of the following Specific Aims: 1) Build on preliminary data to characterize opioid-induced microglial reactivity in vitro. 2) Investigate the mechanism of opioid-induced migration in vitro and in vivo. 3) Determine whether postactivated microglia retain memory and mechanisms to alter responses to subsequent exposure to opioids or stressors. Elucidating the mechanisms of opioid tolerance has the potential to aid a large patient population not served by current drugs by providing new targets for drug discovery. Taken together, these studies will provide a comprehensive and multidisciplinary approach to investigate the influence of CNS neuroimmune activation, specifically microglial reactivity on opioid tolerance and opioid-induced hyperalgesia. The data from these proposed studies will provide important new information and may culminate in novel pharmacopeia to reduce opioid tolerance. In addition, the results may have a more far-reaching impact on understanding CNS plasticity that occurs during opioid drug addiction. PUBLIC HEALTH RELEVANCE: The primary purpose of this proposal is to identify the effects of drugs of abuse (i.e. opioids) on glial cell mechanisms that contribute to drug-induced hyperalgesia and tolerance. These studies may also aid in elucidating substance abuse-induced plasticity, the physiological correlate to craving and relapse in drug addiction.

描述（由申请人提供）：本提案的主要目的是确定滥用药物（即阿片类药物）对神经胶质细胞机制的影响，从而导致药物性痛觉过敏和耐受性。这些研究也有助于阐明药物滥用引起的可塑性，以及与药物成瘾的渴望和复发的生理关联。神经胶质细胞（特别是小胶质细胞和星形胶质细胞）曾经被认为只在中枢神经系统中起辅助作用，但现在正受到密切的研究，因为它是许多疾病病理的主要贡献者，包括神经性疼痛、阿片类药物耐受性和最近的药物成瘾。在中枢神经系统受到应激（如损伤或外源药物）后，小胶质细胞表现出反应性，表现为表面或胞浆蛋白表达增强、形态改变、增殖和迁移。有人提出，一旦被激活，特定的小胶质细胞保持后激活或启动状态，即它们保留记忆以改变对后续刺激的反应。这可能是慢性给药后阿片类药物耐受和药物成瘾的潜在机制。我们建议通过以下假设来研究小胶质细胞在阿片样物质耐受性中的作用：慢性阿片样物质诱导持续的中枢神经系统小胶质细胞反应性，导致小胶质细胞和伤害性神经元之间的直接信号传导，表现为痛觉过敏和/或耐受性。此外，我们假设这种选择性激活增强了P2X4受体的细胞外ATP/ADP激活，从而启动小胶质细胞迁移。这些迁移细胞产生局部升高的趋化因子（即单核细胞趋化蛋白-1/CCL2）和其他扩散性促炎因子，诱导背角神经元致敏和耐受性形成。我们将利用体外新生皮层和成年脊髓小胶质细胞以及成年大鼠来研究这一假设，并完成以下具体目标：1)建立体外阿片类药物诱导的小胶质细胞反应性的初步数据。2)研究阿片类药物在体外和体内诱导迁移的机制。3)确定激活后的小胶质细胞是否保留记忆以及改变对随后暴露于阿片类药物或应激源的反应的机制。阐明阿片类药物耐受性的机制有可能通过为药物发现提供新的靶点来帮助大量目前药物无法治疗的患者群体。综上所述，这些研究将提供一个全面和多学科的方法来研究中枢神经系统神经免疫激活，特别是小胶质细胞反应性对阿片样物质耐受性和阿片样物质诱导的痛觉过敏的影响。这些拟议研究的数据将提供重要的新信息，并可能最终形成新的药典，以减少阿片类药物耐受性。此外，该结果可能对理解阿片类药物成瘾过程中发生的中枢神经系统可塑性产生更深远的影响。公共卫生相关性：本提案的主要目的是确定滥用药物（即阿片类药物）对神经胶质细胞机制的影响，从而导致药物性痛觉过敏和耐受性。这些研究也有助于阐明药物滥用引起的可塑性，以及与药物成瘾的渴望和复发的生理关联。