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

遭受创伤性脑损伤(TBI)的人患物质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，但 临床研究已经公布的数据表明，阿片类药物作为一种潜在的治疗方法具有积极的好处 颅脑损伤患者的治疗策略。然而，对阿片类药物暴露对神经元影响的担忧 变性也出现在临床前和临床环境中。例如，白质中的损伤 已有关于美沙酮、吗啡和羟考酮过量患者的记录。 我们承认，脑外伤后使用阿片类药物的神经生物学很难在临床上研究。 环境，特别是在伤害前评估可能不可能或不准确的情况下。因此，我们， 建议调查阿片类药物使用的长期影响，我们的动物模型特征良好的重复性 MTBI(r-mTBI)，从而消除了人体研究固有的偏见。因为有令人困惑的数据 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 在我们的r-mTBI翻译模型中，阿片类药物治疗的慢性影响将识别出任何负面或 对神经行为和神经病理的积极影响，并有助于指导未来的非成瘾治疗 干预措施。拟议研究的主要目的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类拮抗剂的慢性效应 (纳洛酮)。此外，该项目将调查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和脑损伤后的情况下仍未得到充分研究 文学作品。除了缓解疼痛外，了解慢性阿片类药物暴露后小胶质细胞的作用可能 也是防止阿片类药物耐受和解释阿片类药物引起的痛敏的一种方法。 在第一个目标中，雄性动物将暴露在5个MTBI或5个假麻醉(对照)中，然后 使用两种建议的阿片激动剂中的一种、阿片拮抗剂或生理盐水治疗6个月 从最后一次受伤后24小时开始。然后在1个月和6个月时对神经行为表现进行评估 受伤后。在第二个目标中，神经病理和生化分析将在6个月后进行评估。 受伤后。对于这两个目标，我们将评估受伤动物和对照动物相同的结果衡量标准。 暴露在每一种药剂下。我们相信这些发现将在这两个领域具有广泛的适用性。 和阿片类药物研究，因为这项研究中产生的数据将进一步加深对复合体的理解 阿片激动剂和拮抗剂慢性暴露与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方面，我们将提供一个框架，从 然后就可以对最重要的细胞和分子机制做出哪些明智的决定 重要的是要以减少脑外伤相关的病理为目标，而且，哪种治疗干预策略 最适合病人。如果发现成瘾阿片类药物有任何好处，那么这将提供动力 开发针对相同途径的非成瘾治疗。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基于 行为和神经病理结果标记物；2)小胶质细胞在慢性应激反应中的作用 通过研究鸦片类药物的形态状态来暴露于鸦片类药物。

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.