Post-TBI Opioid Exposure Exacerbates Chronic Injury-induced Behavioral and Neuroinflammatory Outcomes

在30多万名因创伤性脑损伤（TBI）而遭受创伤的男女军人中， 在最近的冲突中，70-80%的人接受疼痛治疗。那些TBI受伤的退伍军人提供疼痛管理 更有可能接受以类阿片为基础的治疗，并从事风险更高的类阿片使用。的这种增加 患有TBI的退伍军人中处方阿片类药物的使用反映了全国范围内的阿片类药物滥用和依赖危机 并强调需要了解长期的，渐进的赤字，如那些与奖励和 疼痛结果，可能选择性地和不成比例地发生在给予损伤后阿片类药物的TBI患者中 疗法TBI和早期阿片类药物暴露之间协同作用的确切机制尚不清楚，但 最近的数据表明，原型阿片类药物治疗，吗啡，导致活性氧化的激活， 活性氧（ROS）和促炎介质打开了它可以增强或延长诱导的可能性 在TBI后的这些系统中，阿片类药物旨在缓解的病理性疼痛恶化， 以及导致成瘾的脆弱性。[The申请中提供的初步数据支持这一点， 暗示，因为实验性TBI后的吗啡暴露导致皮层神经元的协同升高， ROS和促炎细胞因子白细胞介素1 β的水平高于在任一条件下观察到的水平 在急性损伤后阶段（TBI后7天）单独使用，并与小胶质细胞增加相关。 在更长的时间点（TBI后30天）在皮质中的表达。这些数据进一步证明 调查TBI和亚慢性阿片类药物暴露对长期TBI结局的叠加效应，以及 这表明神经免疫功能的调节剂，如神经胶质衰减剂异丁司特，可以预防或 逆转这些过程和相关的行为缺陷。[The这一建议的核心假设是， 创伤性脑损伤后吗啡暴露将增加损伤诱导的奖赏、疼痛及其相互作用的改变 通过负责这些区域的氧化和炎症系统的加剧招募， 行为，并且这些将通过用神经胶质衰减剂异丁司特的神经治疗干预来逆转。 我们将从三个具体目标来探讨这一假设：（1）评估TBI对患者的长期影响。 整合疼痛和奖赏反应以及损伤后吗啡增强这些结果的能力。（二） 用异丁司特评估神经胶质衰减以改善TBI诱导的疼痛和用异丁司特增强的奖赏反应。 创伤后吗啡(3)量化损伤后吗啡对TBI诱导的氧化应激的影响， 神经炎症和异丁司特减轻这些结果的疗效，在神经奖励和疼痛 中心。]这项工作将建立吗啡急性TBI后加重损伤诱导的氧化应激 以及调节奖赏和疼痛影响的区域的炎症反应， 行为结果确定异丁司特逆转这些长期结果的能力将提供一个 解决退伍军人TBI经历的不同不良后果的治疗框架 在康复期接受阿片类药物治疗疼痛的患者。 康帝-1

Of the more than 300,000 service men and women that have sustained traumatic brain injury (TBI) due to recent conflicts, 70-80% are treated for pain. Those TBI-injured Veterans that are provided pain management are more likely to receive opioid-based treatment and engage in higher-risk opioid use. This increase in prescription opioid use among Veterans with TBI reflects the nationwide opioid abuse and dependence crisis and highlights the need to understand the long-term, progressive deficits, such as those related to reward and pain outcomes, that may selectively and disproportionately occur in TBI patients given post-injury opioid therapy. The exact mechanism(s) underlying a synergy among TBI and early opioid exposure are unknown, but recent data indicating the prototypical opioid therapeutic, morphine, leads to activation of reactive oxidative species (ROS) and pro-inflammatory mediators opens the possibility it could enhance or extend the induction of these systems following TBI, worsening pathological pain for which opioids were intended to alleviate, as well as contributing to addiction vulnerability. [The preliminary data presented in the application support this suggestion, as morphine exposure following experimental TBI resulted in synergistic elevations in cortical levels of ROS and the pro-inflammatory cytokine, interleukin 1 beta, over that observed with either condition alone in the acute post-injury phase (7 days post-TBI), and was associated with increased microglial expression in the cortex at more protracted timepoints (30 days post-TBI).] These data warrant further investigation of the additive effects of TBI and subchronic opioid exposure on long-term TBI outcomes, as well as indicate that modulators of neuroimmune function, such as the glial attenuator ibudilast, could prevent or reverse these processes and associated behavioral deficits. [The central hypothesis of this proposal is that morphine exposure following TBI will heighten injury-induced alterations in reward, pain and their interaction through exacerbated recruitment of oxidative and inflammatory systems in regions responsible for these behaviors, and that these will be reversed by neurotherapeutic intervention with a glial attenuator, ibudilast. This hypothesis will be interrogated with three Specific Aims: (1) Evaluate the long-term impact of TBI on integrated pain and reward responses and the ability of post-injury morphine to potentiate these outcomes. (2) Assess glial attenuation with ibudilast to ameliorate TBI-induced pain and reward responses augmented with post-injury morphine. (3) Quantify the influence of post-injury morphine on TBI-induced oxidative stress and neuroinflammation, and the efficacy of ibudilast to attenuate these outcomes, in neural reward and pain centers.] This work would establish that morphine acutely after TBI exacerbates injury-induced oxidative stress and inflammatory responses in regions mediating reward and pain affect, potentiating these detrimental behavioral outcomes. Identifying the ability of ibudilast to reverse these protracted outcomes would provide a therapeutic framework for addressing the distinct adverse consequences experienced by Veterans with TBI who receive opioids for pain management in the rehabilitative period. Conti-1