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

强啡肽/卡帕阿片受体系统在爆炸诱发的精神病理学中的因果机制和治疗潜力

基本信息

批准号：
10630199
负责人：
Abigail G Schindler
金额：
--
依托单位：
VA PUGET SOUND HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630199
关键词：
Acute Afghanistan Animal Model Basal Cell Behavior Behavioral Biological Chemicals Chronic Chronic stress Clinical Clinical Trials Competitive Binding Cues Data Development Disparate Dopamine Dynorphins Event Executive Dysfunction Explosion Exposure to Female Foundations Functional disorder Funding Goals Impairment Impulsivity Inflammation Injury Investigation Iraq K-Series Research Career Programs Knowledge Mediating Mediator Mental Depression Mental Health Modeling Morbidity - disease rate Motivation Mus Nature Neuroglia Neurons Occupational Opioid Antagonist Outcome Pathology Pharmaceutical Preparations Phase Physiological Play Population Post-Traumatic Stress Disorders Problem behavior Psychopathology Quality of life Receptor Activation Recording of previous events Reporting Research Subjects Risk Rodent Model Role Sex Differences Shock Source Stress System Testing Therapeutic Time Translating Trauma Treatment Efficacy Tube United States Veterans War Work addiction antagonist behavioral impairment behavioral outcome biological adaptation to stress blast exposure clinically relevant cognitive function comorbidity cost daily functioning design dysphoria effective therapy executive function experience flexibility improved insight kappa opioid receptors male mesolimbic system mild traumatic brain injury mortality multimodality negative affect neuropsychiatric disorder neurotransmission new therapeutic target pre-clinical research prophylactic receptor response service member sex social trauma exposure traumatic stress

项目摘要

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.

创伤和慢性压力会导致许多不良的行为和生理结果，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异常高的创伤暴露率，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）。爆炸暴露（通过爆炸）通常是重复性的高爆炸物）是军人创伤的主要来源，通常导致轻度创伤与PTSD高度共病的脑损伤（mTBI，伊拉克和阿富汗战争的“标志性损伤”），抑郁和成瘾 .估计有40万退伍军人有爆炸性mTBI的历史，但预防性除防护装备外，尚不存在其他办法，治疗办法的效力有限。压力会导致厌恶/烦躁（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/κ阿片受体（KOR）系统和随后的适应不良变化，中脑边缘系统这种KOR介导的功能障碍被认为是压力沉淀能力的基础和/或加重与PTSD、抑郁和成瘾相关的精神病理学，但强啡肽/KOR系统还没有被检查作为一个潜在的介导的爆炸诱导的病理。关键是，KOR拮抗剂是目前正在平民中进行临床试验研究，用于治疗与压力有关的精神病理学，但这些药物在爆炸暴露环境中的潜力尚未得到研究。在冲击波mTBI后，通常报告负性情感和执行功能障碍，生活质量和成瘾性行为的潜在风险，但潜在机制尚不清楚明白使用啮齿类动物的原始细胞mTBI模型的临床前研究工作可以提供急需的洞察力，潜在的机制，并提供了一个必要的竞技场的早期测试的潜在治疗化合物.在我获得VA BLR&D职业发展奖期间建立的坚实基础上， 2（CDA 2）资金，目标将通过三个综合具体目标实现：1）确定是否 KOR激活是胚细胞mTBI诱导的冲动性和行为可控制性所必需的（即，执行功能障碍）。2)评估KOR激活是否是胚细胞mTBI诱导的中脑边缘功能障碍所必需的。 3)建立在原始细胞mTBI后长期施用的KOR拮抗作用的治疗功效。这些拟议的研究将首次定义KOR激活在不良冲击波mTBI结局中的作用，突出了该受体系统作为新治疗靶点。获得的知识可以直接翻译，用于为军人和退伍军人开发更有效的治疗方法，有急性脑外伤史