Post-TBI Opioid Exposure Exacerbates Chronic Injury-induced Behavioral andNeuroinflammatory Outcomes

TBI 后阿片类药物暴露会加剧慢性损伤引起的行为和神经炎症结果

基本信息

批准号：
10557861
负责人：
ALANA C. CONTI
金额：
--
依托单位：
JOHN D DINGELL VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10557861
关键词：
Absence of pain sensation Acute Address Affect Amygdaloid structure Animals Anterior Anxiety Astrocytes Attenuated Behavior Behavioral Brain Injuries Chronic Clinical Data Dependence Dose Exposure to Freedom Functional disorder Generations Goals Hour Human Resources Inflammation Mediators Inflammatory Inflammatory Response Injury Interleukin-1 beta Intervention Investigation Knowledge Link Measures Medial Mediating Mediator Mental Depression Microglia Morphine Morphology Multiple Sclerosis Mus NADPH Oxidase Neuroglia Neuroimmune Nucleus Accumbens Operative Surgical Procedures Opiate Addiction Opioid Outcome Oxidative Stress Oxidative Stress Induction Pain Pain Clinics Pain management Pathologic Pathology Pathway interactions Pattern Persistent pain Pharmaceutical Preparations Phase Predisposition Prefrontal Cortex Procedures Process Quality of life Recovery of Function Regimen Rehabilitation therapy Reporting Rewards Risk Saline Serum Services Signal Transduction Stimulus Suggestion System TBI Patients Tail Suspension Testing Therapeutic Tissues Traumatic Brain Injury Ventral Tegmental Area Veterans Woman Work active duty addiction adverse outcome attenuation behavior test behavioral outcome behavioral response biological adaptation to stress cingulate cortex cohort combat conditioned place preference cytokine design experience functional disability functional outcomes glial activation hedonic high risk improved injured innovation men midbrain central gray substance neural neuroadaptation neuroinflammation neuropsychiatry novel strategies operation opioid abuse opioid exposure opioid misuse opioid therapy opioid use pain outcome pain relief preference prescription opioid prevent recruit response service member synergism therapeutic opioid

项目摘要

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

由于有30万以上的服务男女在脑损伤（TBI）最近的冲突，有70-80％的疼痛治疗。那些提供疼痛管理的TBI受伤的退伍军人更有可能接受基于阿片类药物的治疗并从事高风险的阿片类药物使用。这增加了有TBI退伍军人的处方阿片类药物使用反映了全国性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，例如与奖励和奖励相关的赤字疼痛结果，在受伤后阿片类药物的TBI患者中可能有选择和不成比例地发生治疗。 TBI和早期阿片类药物暴露之间的协同作用的确切机制尚不清楚，但最新数据表明原型阿片类药物治疗，吗啡导致反应性氧化激活物种（ROS）和促炎性介体可以增强或扩展诱导的可能性在TBI之后的这些系统中，阿片类药物旨在减轻的病理疼痛恶化，如以及为成瘾脆弱性做出贡献。 [应用程序中介绍的初步数据支持此建议，由于实验性TBI后吗啡的暴露导致皮质的协同升高 ROS和促炎细胞因子的水平介绍了两种条件下观察到的水平。单独在急性伤害后阶段（TBI 7天），与小胶质细胞增加有关这些数据在更旷日持久的时间点（TBI 30天）中的皮质表达。]这些数据还需要进一步还研究了TBI和亚基量阿片类药物对长期TBI结局的添加作用的研究，这表明神经免疫功能的调节剂，例如神经胶质衰减剂ibudilast，可以预防或扭转这些过程和相关的行为缺陷。 [该提议的核心假设是 TBI之后的吗啡暴露将增加受伤引起的奖励，疼痛及其相互作用的改变通过加剧负责这些地区的氧化和炎症系统的募集行为，这些行为将通过神经胶质衰减剂Ibudilast逆转。该假设将通过三个具体目的审问：（1）评估TBI对综合的疼痛和奖励反应以及后伤后吗啡增强这些结果的能力。（2）用ibudilast评估神经胶质衰减，以改善TBI引起的疼痛和奖励反应增加后吗啡。（3）量化伤害后吗啡对TBI诱导的氧化应激和神经炎症，以及ibudilast的疗效减轻这些结果，在神经奖励和疼痛方面中心。]这项工作将确定TBI加剧损伤引起的氧化应激后的吗啡以及介导奖励和疼痛影响的地区的炎症反应，增强了这些有害的行为结果。确定ibudilast扭转这些旷日持久的结果的能力将提供用于解决TBI退伍军人所遇到的明显不利后果的治疗框架在康复期内接受阿片类药物进行疼痛管理。 conti-1