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

在30多万名因以下原因而遭受创伤性脑损伤(TBI)的军人中 最近的冲突中，70%-80%的人因疼痛而接受治疗。那些接受疼痛治疗的颅脑损伤退伍军人 更有可能接受阿片类药物治疗，并从事风险更高的阿片类药物使用。这一增长 退伍军人脑损伤患者处方类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、渐进的赤字，如与奖励和 创伤后服用阿片类药物的脑损伤患者可能选择性和不成比例地发生的疼痛结果 心理治疗。脑外伤和早期阿片类药物暴露之间协同作用的确切机制(S)尚不清楚，但 最近的数据表明，典型的阿片类药物吗啡会导致反应性氧化的激活 物种(ROS)和促炎介质开启了增强或延长诱导的可能性 在颅脑损伤后的这些系统中，阿片类药物旨在缓解的病理性疼痛恶化，如 而且还会增加上瘾的脆弱性。[申请书中提供的初步数据支持这一点 建议，因为实验性脑创伤后吗啡暴露导致皮层协同升高 ROS和促炎细胞因子IL-1β的水平高于任何一种情况 仅在急性损伤后阶段(脑损伤后7天)，并与小胶质细胞增加有关 在更长的时间点(脑损伤后30天)皮质中的表达。]这些数据进一步证明了 脑损伤和亚慢性阿片类药物暴露对脑损伤长期结局的相加影响的研究 AS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。[这项提议的中心假设是 颅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 通过加剧氧化和炎症系统在负责这些区域的招募 这些行为将通过神经胶质衰减剂异丁司特的神经治疗干预而逆转。 这一假设将受到三个具体目标的质疑：(1)评估TBI对 综合疼痛和奖赏反应以及损伤后吗啡增强这些结果的能力。(2) 使用异丁司特评估胶质细胞衰减以改善颅脑损伤引起的疼痛和奖赏反应 受伤后的吗啡。(3)量化损伤后吗啡对颅脑损伤后氧化应激的影响。 神经炎症，以及异丁司特在神经奖赏和疼痛中减轻这些结果的有效性 中心。]这项工作将证实，在脑损伤后，吗啡急剧加剧了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，加剧了这些有害的 行为结果。确定异丁司特逆转这些旷日持久的结果的能力将提供 解决退伍军人脑外伤患者所经历的不同不良后果的治疗框架 他们在康复期接受阿片类药物治疗疼痛。 CONTI-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