Causal mechanism and therapeutic potential of the dynorphin/kappa opioid receptor system in blast-induced psychopathology

创伤和慢性压力会导致许多不良的行为和生理后果，导致 发病率/死亡率增加，社会和职业功能受损。军人和退伍军人 经历过极高的创伤暴露，这可能会加速和/或加剧随后的 神经精神障碍(即精神病理学)。在性质上最常见的是重复性，爆炸暴露(通过引爆 烈性炸药)是军人创伤的主要来源，通常导致轻微创伤 脑损伤(mTBI，伊拉克和阿富汗战争的“标志性损伤”)，与创伤后应激障碍高度共存， 抑郁和上瘾 。据估计，有40万退伍军人有爆炸伤的病史，但采取了预防性措施 除了防护装备之外，目前还不存在其他方法，治疗方案的效果有限。压力可以 导致厌恶/烦躁不安(一种深刻的不安或不满状态)，主要通过激活来调节 内源性强啡肽/kappa阿片受体(KOR)系统和随后的适应不良变化 中边缘系统。这种KOR介导的功能障碍被认为是压力沉淀能力的基础 和/或加剧与创伤后应激障碍、抑郁和成瘾相关的精神病理，但强啡肽/KOR系统 还没有被认为是冲击波诱导病理的潜在介体。关键的是，韩国的对手是 目前正在对平民人群进行临床试验研究，以治疗与应激有关的疾病 精神病理学，但这些药物在爆炸暴露环境中的潜力尚未被检查。 冲击性mTBI后，通常会有负面情绪和执行功能障碍的报道，导致减少 生活质量和类似成瘾行为的潜在风险，但潜在的机制尚不清楚 明白了。使用BLAST mTBI啮齿动物模型的临床前研究工作可以提供急需的洞察 潜在的机制，并为潜在治疗方法的早期测试提供了必要的舞台 化合物。以我在VA BLR&D职业发展奖期间建立的坚实基础为基础 2(CDA2)供资，目标将通过三个综合的具体目标来实现：1)确定 冲击波mTBI诱发的冲动和行为僵化(即执行)需要KOR激活 功能障碍)。2)探讨冲击性mTBI所致的中脑边缘功能障碍是否需要KOR激活。 3)建立冲击性mTBI后长期应用KOR拮抗剂的治疗效果。这些 拟议的研究将首次确定KOR激活在不利的冲击性mTBI结局中的作用，以及 强调这个受体系统是一个新的治疗靶点。所获得的知识可以直接翻译和 用于开发更有效的治疗军人和退伍军人 爆炸mTBI的历史。

Trauma and chronic stress results in a multitude of adverse behavioral and physiological outcomes, leading to increased morbidity/mortality and impaired social and occupational functioning. Servicemembers and Veterans experience exceptionally high rates of trauma exposure, which can precipitate and/or exacerbate subsequent neuropsychiatric disorders (i.e., psychopathology). Most often repetitive in nature, blast exposure (via detonation of high explosives) represents a major source of trauma for Servicemembers, often resulting in mild traumatic brain injury (mTBI, the “signature injury” of the Iraq and Afghanistan wars) that is highly comorbid with PTSD, depression, and addiction . An estimated 400,000 Veterans have a history of blast mTBI, but prophylactic approaches, other than protective gear, do not yet exist, and treatment options have limited efficacy. Stress can result in aversion/dysphoria (a profound state of unease or dissatisfaction), mediated largely through activation of the endogenous dynorphin/kappa opioid receptor (KOR) system and subsequent maladaptive changes within the mesolimbic system. This KOR-mediated dysfunction is thought to underlie the ability of stress to precipitate and/or exacerbate psychopathology related to PTSD, depression, and addiction, but the dynorphin/KOR system has not been examined as a potential mediator of blast-induced pathology. Critically, KOR antagonists are currently under clinical trial investigation in the civilian population for treatment of stress-related psychopathology, but the potential of these drugs in a blast exposure setting has not yet been examined. Negative affect and executive dysfunction are commonly reported following blast mTBI, leading to decreased quality of life and potential risk for addictive-like behaviors, but the underlying mechanisms are not well understood. Preclinical research efforts using rodent models of blast mTBI can provide much needed insight into underlying mechanisms and provide an essential arena for early-stage testing of potential therapeutic compounds. Building upon the strong foundation established during my VA BLR&D Career Development Award 2 (CDA2) funding, goals will be accomplished through three integrated Specific Aims: 1) to determine whether KOR activation is required for blast mTBI-induced impulsivity and behavioral inflexibility (i.e., executive dysfunction). 2) to evaluate whether KOR activation is required for blast mTBI-induced mesolimbic dysfunction. 3) to establish therapeutic efficacy of KOR antagonism administered chronically following blast mTBI. These proposed studies will define, for the first time, the role of KOR activation in adverse blast mTBI outcomes and highlight this receptor system as a novel therapeutic target. Knowledge gained can be directly translated and utilized towards the development of more effective treatment approaches for Servicemembers and Veterans with a history of blast mTBI.