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: 10217284
• 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/10217284
• 关键词: Address; Age-Months; Anesthesia procedures; Animal Model; Animals; Anxiety; Area; Behavioral; Biochemical; Biochemical Markers; Biological; Brain Concussion; Brain Injuries; Caring; Cells; Chronic; Clinical; Clinical Data; Cognitive; Complex; Conflict (Psychology); Control Animal; Data; Demyelinations; Development; Disease; Dose; 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; Oxycodone; Pain; Pathologic; Pathology; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Pharmacology; 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 treatment; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Traumatic Brain Injury; Veterans; addiction; axon injury; base; chronic pain; clinical investigation; 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; 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.

遭受创伤性脑损伤（TBI）的人面临较高的物质使用障碍的风险， 尽管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 临床研究已经发布了数据，表明阿片类药物作为潜在治疗的积极好处 TBI患者的策略。但是，对阿片类药物暴露对神经元的影响的担忧 在临床前和临床环境中也出现了变性。例如，白质病变 已记录了美沙酮，吗啡和羟考酮过度剂量的患者。 我们承认，TBI后的阿片类药物使用神经生物学很难在临床上研究 设置，尤其是在不可能或准确的情况下评估的情况下。因此，我们 建议研究阿片类药物使用在我们的重复性良好动物模型中的长期影响 MTBI（R-MTBI），从而消除了人类研究固有的偏见。由于有混杂的数据 阿片类药物治疗或滥用对R-MTBI之后慢性结局的影响我们假设对 阿片类药物治疗在我们的R-MTBI翻译模型中的慢性影响将确定任何负面或 对神经行为和神经病理学的积极影响，并有助于指导未来，非依恋，治疗 干预措施。拟议研究的总体目的是调查和完善我们对 两种阿片类激动剂（羟考酮，美沙酮）和非选择性鸦片拮抗剂的慢性作用 （纳洛酮）。此外，该项目将研究小胶质细胞与阿片类药物之间的相互作用。但是角色 在长期阿片类药物治疗和脑损伤之后的小胶质细胞中仍未遭受 文学。除了缓解疼痛外，了解小胶质细胞在慢性阿片类药物暴露后的作用可能 也是一种预防阿片类药物耐受性并解释阿片类药物诱导的女痛性的方法。 在第一个目标中，雄性动物将暴露于五个mtbis或五个假麻醉（对照组），然后 用两种拟议的阿片类药物激动剂之一，阿片类药物拮抗剂或盐水治疗6个月 开始后腹部受伤24小时。然后，将在1个月和6个月内评估神经行为的性能 伤害后。在第二个目标中，将在6个月时评估神经病理学和生化分析 伤害后。对于这两个目标，我们将评估受伤动物与对照动物的相同结果指标 暴露于每种药理剂。我们认为这些发现在两个TBI中都有广泛的适用性 和阿片类药物研究，因为本研究中产生的数据将进一步了解复杂 阿片类药物激动剂和拮抗剂，TBI和小胶质细胞的慢性暴露之间的相互作用 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，可以对最明智的决定做出有关最多的细胞和分子机制的决定 对于减少与TBI相关的病理学以及哪种治疗性干预策略的目标至关重要 最适合患者。如果在上瘾的阿片类药物中发现任何好处，那么这将为 针对相同途径的非依恋治疗的发展。从开始日期开始的18个月内 这个项目，我们将能够确定：1）哪种阿片类药物（如果有）提供最佳的基于神经系统恢复 关于行为和神经病理学结果标记； 2）小胶质细胞对慢性的作用 通过研究其形态状态来暴露于阿片类药物。