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: 7586380
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586380
• 关键词: Adult; Adverse effects; Analgesics; Astrocytes; Attenuated; Biological Assay; CCL2 gene; Cells; Chronic; Class; 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; Patients; Pharmaceutical Preparations; Pharmacopoeias; Physiologic pulse; Physiological; Population; Posterior Horn Cells; Public Health; Pulse taking; Purinoceptor; Purpose; Rattus; Receptor Activation; Regulation; Relapse; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Spinal; Stress; Surface; Thinking; Time; Western Blotting; Xenobiotics; addiction; chemokine; chronic pain; concept; 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; protein expression; 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）对神经胶质细胞机制的影响，从而导致药物引起的痛觉过敏和耐受。这些研究还可能有助于阐明药物滥用引起的可塑性，即与毒瘾的渴望和复发的生理相关性。神经胶质细胞（特别是小胶质细胞和星形胶质细胞）一度被认为仅在中枢神经系统中发挥支持作用，但现在正受到密切的研究，因为它们是许多疾病病理学的主要贡献者，包括神经性疼痛、阿片类药物耐受性和最近的药物成瘾。中枢神经系统受到应激（例如损伤或外源性给药）后，小胶质细胞会变得反应性，表现为表面或胞浆蛋白表达增强、形态变化、增殖和迁移。有人提出，一旦激活，特定的小胶质细胞就会保持激活后或启动状态，即它们保留改变对后续刺激的反应的记忆。这可能是长期给药和药物成瘾后阿片类药物耐受的潜在机制。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中的作用：慢性阿片类药物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。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，诱导背角神经元敏化和耐受性形成。将使用体外原代新生儿皮质和成年脊髓小胶质细胞、体内成年大鼠并通过完成以下具体目标来研究总体假设：1）基于初步数据来表征阿片类药物诱导的体外小胶质细胞反应性。 2）研究阿片类药物诱导体内外迁移的机制。 3）确定激活后的小胶质细胞是否保留记忆和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机制有可能通过为药物发现提供新靶点来帮助目前药物无法治疗的大量患者群体。总而言之，这些研究将提供一种全面的多学科方法来研究中枢神经系统神经免疫激活的影响，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引起的痛觉过敏的影响。这些拟议研究的数据将提供重要的新信息，并可能最终产生减少阿片类药物耐受性的新药典。此外，这些结果可能对理解阿片类药物成瘾期间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：该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，从而导致药物引起的痛觉过敏和耐受。这些研究还可能有助于阐明药物滥用引起的可塑性，即与毒瘾的渴望和复发的生理相关性。