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）的个体患药物使用障碍的风险更高， 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， 临床研究已经发表了表明阿片类药物作为潜在治疗药物的积极益处的数据 TBI患者的治疗策略然而，关于阿片类药物暴露对神经元的影响， 退化也出现在临床前和临床环境中。例如，白色物质中的病变 已记录美沙酮、吗啡和羟考酮过量患者。 我们承认，TBI后阿片类药物使用的神经生物学在临床上很难研究。 特别是在伤前评估可能不可能或不准确的情况下。因此， 建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），从而消除了人体研究固有的偏倚。由于存在关于 阿片类药物治疗或滥用对r-mTBI后慢性结局影响我们假设研究 阿片类药物治疗在我们的r-mTBI转化模型中的慢性作用将鉴定任何阴性或 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性治疗 干预措施。拟议研究的总体目标是调查和完善我们对 两种阿片激动剂（羟考酮、美沙酮）和一种非选择性阿片拮抗剂的慢性效应 （纳洛酮）。此外，该项目将研究小胶质细胞和阿片类药物之间的相互作用;然而， 小胶质细胞在长期阿片类药物治疗的背景下和脑损伤后的作用仍有待研究。 文学作品除了缓解疼痛，了解小胶质细胞在慢性阿片类药物暴露后的作用可能 也是防止阿片耐受和解释阿片诱导的痛觉过敏的一种方法。 在第一个目标中，雄性动物将暴露于5次mTBI或5次假麻醉（对照），然后 用两种建议的阿片激动剂之一、阿片拮抗剂或生理盐水治疗6个月 从上次受伤后24小时开始。然后在1个月和6个月时评估神经行为表现 受伤后。在第二个目标中，将在6个月时评价神经病理学和生化分析 受伤后。对于这两个目标，我们将在受伤动物与对照动物中评价相同的结局指标 暴露于每种药理学试剂。我们相信这些发现将在TBI和TBI中具有广泛的适用性。 和阿片类药物的研究，因为这项研究产生的数据将进一步了解复杂的 阿片受体激动剂和拮抗剂慢性暴露与脑外伤和小胶质细胞的相互作用 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， 然后可以对最常见的细胞和分子机制做出明智的决定， 重要是以减少TBI相关病理为目标，此外， 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性治疗方法。自开始日期起计18个月内 这个项目，我们将能够确定：1）哪些阿片类药物，如果有的话，提供最好的神经恢复的基础 行为和神经病理学结果标记; 2）小胶质细胞在慢性炎症反应中的作用 通过研究它们的形态学状态来暴露于阿片类药物。