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）：该提案的主要目的是确定滥用药物（即阿片类药物）对有助于药物引起的痛觉过敏和耐受性的神经胶质细胞机制的影响。这些研究还可能有助于阐明药物滥用引起的可塑性，生理与渴望和药物成瘾的复发相关。一旦被认为仅在中枢神经系统中发挥支持作用，神经胶质细胞（特别是小胶质细胞和星形胶质细胞）现在正在接受激烈的研究，这是对许多疾病的主要因素，包括神经性疼痛，阿片类药物耐受性，以及最近的疾病。随着CNS的压力（例如损伤或异种施用）小胶质细胞的反应性，如表面或胞质蛋白表达增强，形态变化，增殖和迁移所定义。已经提出，一旦激活，特定的小胶质细胞保持后激活或底漆，即它们保留记忆以改变对后续刺激的反应。这可能是长期给药后阿片类药物耐受性的潜在机制以及药物成瘾。我们建议通过研究以下假设来研究小胶质细胞在阿片类药物耐受性中的作用：慢性阿片类药物会诱导持续的CNS小胶质细胞反应性，从而导致小胶质细胞和伤害性神经元之间直接信号传导，这些神经元表现为近似和/或耐受性。此外，我们假设这种选择性激活增强了启动小胶质细胞迁移的P2X4受体的细胞外ATP/ADP激活。这些迁移的细胞产生局部升高的趋化因子（即单核细胞趋化剂蛋白-1/CCL2）和其他可扩散的促炎因子，从而诱导背角神经元神经元敏感和耐受性形成。总体假设将使用体外原发性新生儿皮质和成人脊柱小胶质细胞，体内大鼠以及以下特定目的完成：1）基于初步数据，以表征阿片类药物诱导的小胶质细胞反应性。 2）研究阿片类药物诱导的体外和体内迁移的机制。 3）确定小胶质细胞是否保留记忆和机制，以改变对随后暴露于阿片类药物或压力源的反应。阐明阿片类药物耐受性的机制有可能通过提供新的药物发现靶标的目前药物提供的大量患者人群。综上所述，这些研究将提供一种全面的多学科方法，以研究中枢神经系统神经免疫性激活的影响，特别是小胶质细胞反应性对阿片类药物耐受性和阿片类药物诱导的女痛性的影响。这些提出的研究的数据将提供重要的新信息，并可能在新型药物中达到最终水平，以降低阿片类药物的耐受性。此外，结果可能会对理解阿片类药物成瘾期间发生的CNS可塑性产生更深远的影响。公共卫生相关性：该提案的主要目的是确定滥用药物（即阿片类药物）对有助于药物引起的痛苦和耐受性的神经胶质细胞机制的影响。这些研究还可能有助于阐明药物滥用引起的可塑性，生理与渴望和药物成瘾的复发相关。