Long-term effects of opioid use in a mouse model of repetitive mild traumatic brain injury

阿片类药物使用对重复性轻度创伤性脑损伤小鼠模型的长期影响

• 批准号: 10684627
• 负责人: Benoit Christian Mouzon
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10684627
• 关键词: Age Months; Anesthesia procedures; Animal Model; Animals; Anxiety; Area; Behavioral; Biochemical; Biochemical Markers; Biological; Brain Concussion; Brain Injuries; Caring; Cells; Chronic; Clinical; Cognitive; Complex; Control Animal; Data; Demyelinations; Development; Disease associated microglia; Dose; Euthanasia; Evaluation; Exhibits; Exposure to; Future; Gliosis; Goals; Hour; Human; Hyperalgesia; Implant; Individual; Injury; Intervention; Investigation; K-Series Research Career Programs; Knowledge; Lesion; Literature; Long-Term Effects; Maze Learning; Measures; Mediating; Medical; Methadone; Microglia; Molecular; Morphine; Morphology; Mus; Naloxone; Nerve Degeneration; Neurobiology; Neuroglia; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Antagonist; Opioid agonist; Outcome; Outcome Measure; Overdose; Oxycodone; Pain; Pathologic; Pathology; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Polysomnography; Population; Post-Traumatic Stress Disorders; Pre-Clinical Model; Publishing; Pump; Recording of previous events; Recovery; Research; Research Personnel; Resolution; Role; Saline; Sleep disturbances; Social Interaction; Substance Use Disorder; TBI Patients; TBI treatment; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Traumatic Brain Injury; Veterans; addiction; antagonist; axon injury; chronic pain; cognitive benefits; cognitive function; cytokine; high risk; injured; insight; male; meter; mild traumatic brain injury; millisecond; mimetics; mouse model; neurobehavior; neurobehavioral; neuroinflammation; neurological recovery; neuropathology; opiate tolerance; opioid abuse; opioid exposure; opioid use; osmotic minipump; pain relief; patient population; pharmacologic; placebo group; pre-clinical; preclinical study; prescription opioid; prevent; response; response to injury; tau Proteins; transcriptome; translational model; white matter; white matter injury

Individuals who have sustained a traumatic brain injury (TBI) are at a higher risk for substance use disorders, and while clinicians and researchers widely acknowledge issues with opioid abuse and dependence, pre- clinical investigations have published data suggesting positive benefits of opioids as a potential therapeutic strategy for patients of TBI. However, concerns regarding the effect of opioid exposure on neuronal degeneration have also emerged in both pre-clinical and clinical settings. For example, lesions in white matter have been documented for methadone, morphine and oxycodone over-dosed patients. We acknowledge that the neurobiology of opioid use following TBI is difficult to study in clinical settings, especially in cases where pre-injury assessment may not be possible or accurate. We, therefore, propose to investigate the long-term effects of opioid use in our well-characterized animal model of repetitive mTBI (r-mTBI), thereby removing the biases inherent to human studies. As there are confounding data on the influence of opioid treatment or abuse on chronic outcomes after r-mTBI we hypothesize that investigation of the chronic effects of opioid treatment in our translational model of r-mTBI will identify any negative or positive effects on neurobehavior and neuropathology and help guide future, non-addictive, treatment interventions. The overarching aim of the proposed study is to investigate and refine our understanding of the chronic effects of two opioid agonists (Oxycodone, Methadone), and a non-selective opiate antagonist (Naloxone). In addition, this project will investigate the interaction between microglia and opioids; yet the role of microglia in the context of long-term opioid treatment and after brain injuries remains underexplored within the literature. In addition to pain relief, understanding the role of microglia after chronic opioid exposure might also be a way to prevent opioid tolerance and explain opioid induced hyperalgesia. In the first aim, male animals will be exposed to five mTBIs or five sham anesthesia (controls), and then treated with one of the two proposed opioid agonists, an opioid antagonist, or saline for a period of 6 months starting 24h post-last injury. The neurobehavioral performance will then be evaluated at both 1- and 6-months post-injury. In the second aim, neuropathological and biochemical analyses will be evaluated at 6 months post-injury. For both aims, we will evaluate the same outcome measures in injured versus control animals exposed to each pharmacological agent. We believe these findings will have broad applicability in both TBI and opioid research, as the data generated in this study will further the understanding of the complex interaction between the chronic exposure of opioid agonists and antagonist, TBI and the microglia cell population. By assessing nuanced aspects of neurobehavioral and pathological deficits, we will provide a framework from which informed decisions can then be made about the cellular and molecular mechanisms that are most important to target to reduce TBI-related pathology, and furthermore, which therapeutic intervention strategy best suits the patient. If any benefits are found with addictive opioids, then this will provide the impetus for development of non-addictive treatments targeting the same pathways. Within 18 months from the start date of this project, we will be able to determine: 1) Which opioids if any, provide the best neurological recovery based on the behavioral and neuropathological outcome markers; and 2) the role of microglia in response to chronic exposure to opiates by studying their morphological states.

遭受过创伤性脑损伤 (TBI) 的个体出现物质使用障碍的风险较高， 虽然临床医生和研究人员广泛承认阿片类药物滥用和依赖的问题，但 临床研究已发表的数据表明阿片类药物作为潜在治疗方法具有积极的益处 TBI 患者的治疗策略。然而，人们担心阿片类药物暴露对神经元的影响 临床前和临床环境中也出现了变性。例如，白质病变 已有关于美沙酮、吗啡和羟考酮过量患者的记录。 我们承认 TBI 后阿片类药物使用的神经生物学很难在临床中研究 环境，特别是在受伤前评估可能无法或不准确的情况下。因此，我们 提议在我们充分表征的重复性动物模型中研究阿片类药物使用的长期影响 mTBI (r-mTBI)，从而消除人类研究固有的偏差。由于存在令人困惑的数据 阿片类药物治疗或滥用对 r-mTBI 后慢性结局的影响我们假设调查 阿片类药物治疗在我们的 r-mTBI 转化模型中的慢性影响将识别任何负面或 对神经行为和神经病理学产生积极影响，并有助于指导未来的非成瘾治疗 干预措施。拟议研究的总体目标是调查和完善我们对 两种阿片类激动剂（羟考酮、美沙酮）和一种非选择性阿片拮抗剂的慢性影响 （纳洛酮）。此外，该项目还将研究小胶质细胞和阿片类药物之间的相互作用；但角色 长期阿片类药物治疗和脑损伤后小胶质细胞的变化仍未得到充分研究 文学。除了缓解疼痛之外，了解慢性阿片类药物暴露后小胶质细胞的作用可能会 也是预防阿片类药物耐受并解释阿片类药物引起的痛觉过敏的一种方法。 在第一个目标中，雄性动物将接受五次 mTBI 或五次假麻醉（对照），然后 使用两种建议的阿片受体激动剂之一、阿片受体拮抗剂或生理盐水治疗 6 个月 从上次受伤后 24 小时开始。然后将在 1 个月和 6 个月时评估神经行为表现 受伤后。第二个目标是在 6 个月时评估神经病理学和生化分析 受伤后。为了这两个目标，我们将评估受伤动物与对照动物的相同结果指标 暴露于每种药物。我们相信这些发现将在 TBI 和 TBI 中具有广泛的适用性 和阿片类药物研究，因为本研究生成的数据将进一步了解复杂的 长期暴露阿片类激动剂和拮抗剂、TBI 和小胶质细胞之间的相互作用 人口。 通过评估神经行为和病理缺陷的细微差别，我们将提供一个框架 然后可以对最重要的细胞和分子机制做出明智的决定 减少 TBI 相关病理的目标很重要，此外，哪种治疗干预策略 最适合患者。如果发现成瘾性阿片类药物有任何好处，那么这将为 开发针对相同途径的非成瘾治疗方法。自开始日期起 18 个月内 在这个项目中，我们将能够确定：1）哪种阿片类药物（如果有）可以提供最佳的神经恢复效果 关于行为和神经病理结果标记； 2）小胶质细胞在慢性疾病反应中的作用 通过研究阿片剂的形态状态来接触阿片剂。