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

点击翻译按钮获取中文摘要

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.