Preliminary in vivo investigation of the opioid system in borderline personality disorder

边缘性人格障碍中阿片类药物系统的初步体内研究

• 批准号: 10317111
• 负责人: Margaret Taylor Davis
• 金额: $ 20.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317111
• 关键词: Address; Affect; Affective; Agonist; Amygdaloid structure; Analgesics; Animals; Anterior; Anti-Anxiety Agents; Antidepressive Agents; Attention; Autopsy; Behavior; Binding; Borderline Personality Disorder; Brain; Brain imaging; Brain region; Chronic; Clinical Trials; Cognitive; Control Groups; Depressed mood; Development; Disease; Distress; Dopamine; Down-Regulation; Dynorphins; Feeling suicidal; Frequencies; Functional disorder; Funding; General Population; Goals; High Prevalence; Human; Image; Imaging Techniques; Impulsivity; Individual; Injections; Intervention; Investigation; Life; Link; Low Prevalence; Magnetic Resonance Imaging; Measurement; Mediating; Molecular; Molecular Target; Morbidity - disease rate; Naltrexone; Opioid; Opioid Antagonist; Opioid Peptide; Pain; Pain Threshold; Participant; Peripheral; Pharmaceutical Preparations; Pharmacology; Play; Positron-Emission Tomography; Prefrontal Cortex; Prevention; Psychopathology; Recording of previous events; Regulation; Reporting; Resistance; Risk; Role; Savings; Scanning; Self-Injurious Behavior; Severities; Social Functioning; Stress; Suicide; Suicide attempt; Symptoms; System; Testing; Time; Underserved Population; Validation; Work; abuse liability; base; clinically relevant; drug misuse; drug of abuse; emotion dysregulation; emotion regulation; endogenous opioids; endophenotype; epidemiology study; experience; falls; high risk; high risk population; imaging study; in vivo; innovation; insight; interest; kappa opioid receptors; mu opioid receptors; neuroimaging; novel; opioid mortality; opioid use; pain perception; parametric imaging; preclinical study; psychiatric symptom; radioligand; radiotracer; receptor-mediated signaling; reduce symptoms; reducing suicide; social; stress related disorder; suicidal; suicidal behavior; suicidal morbidity; suicidal risk; suicide mortality; symptom treatment; symptomatology; targeted agent; therapy development; treatment risk

PROJECT SUMMARY The goal of this study is to investigate the role of the kappa opioid receptor (KOR) in the symptomatology of borderline personality disorder (BPD), a condition associated with alarmingly elevated risk for suicide attempt (up to 75%) and death by suicide (up to 10%). Despite BPD’s relatively low prevalence (1-5%), an epidemiological study reported that more than two thirds of recent suicide attempts occurred in individuals with BPD. Unfortunately, most of the available treatments are not capable of addressing overall BPD symptom severity or rapidly reducing suicide risk. Magnetic resonance imaging studies have identified structural and network alterations in BPD symptom presentation and have associated fronto-limbic circuit dysregulation with an increase in BPD symptom severity. Investigation of molecular mechanisms responsible for BPD symptoms, and suicide risk specifically is an essential next step to both promote development of novel treatments and facilitate risk prevention in BPD. Emerging evidence implicates KOR in BPD and suicidal behavior. KOR plays critical roles in emotion regulation, social functioning, and pain perception – all of which are both central to BPD and related to suicide risk. Postmortem studies have shown an association between KOR and death by suicide. Further, a variety of studies in both animals and humans have shown that KOR targeted medications can produce antidepressant, anxiolytic, and even anti-suicidal effects. Importantly, KOR agents’ effect on dopamine is modest relative to drugs of abuse, reducing concerns about abuse potential. Here, we propose a novel investigation of KOR availability of in individuals with BPD using positron emission tomography (PET), a brain imaging technique, and radioligand [11C]EKAP which binds selectively to KOR in the brain (Aim 1). Given the high prevalence of suicide-related behavior in BPD, we will also evaluate the association between KOR availability, suicide attempt history, and current suicidal thoughts in BPD (Aim 2). Lastly, we will evaluate the association between impulsivity, pain tolerance, and self-injury – key endophenotypes of BPD and which are resistant to treatment – and KOR availability (Aim 3). Results of this study will provide potentially critical insight into the relationship between this novel molecular target, BPD symptom presentation, and suicidal behavior. Based on findings we will pursue funding for a larger PET study to test potential non-addictive KOR targeted medications for both overall BPD symptom reduction, and suicide risk.

项目摘要 本研究的目的是探讨κ阿片受体（KOR）在神经病理学中的作用 边缘型人格障碍（BPD），一种与自杀风险惊人升高相关的疾病， 自杀未遂（高达75%）和自杀死亡（高达10%）。尽管BPD的患病率相对较低（1-5%）， 一项流行病学研究报告说，最近三分之二以上的自杀企图发生在患有 波士顿警局不幸的是，大多数现有的治疗方法不能解决整体BPD症状 严重程度或迅速降低自杀风险。磁共振成像研究已经确定了结构和 BPD症状表现的网络改变，并与额叶边缘回路失调相关， BPD症状严重程度增加。研究BPD症状的分子机制， 特别是自杀风险是促进新疗法开发的重要下一步， 促进BPD的风险预防。 新出现的证据表明KOR与BPD和自杀行为有关。KOR在情绪中起着关键作用 调节，社会功能和疼痛感知-所有这些都是BPD的核心，并与自杀有关 风险尸检研究表明KOR与自杀死亡之间存在关联。此外，各种 在动物和人类中的研究已经表明KOR靶向药物可以产生抗抑郁药， 抗焦虑甚至抗自杀的作用重要的是，KOR试剂对多巴胺的影响相对于 药物滥用，减少对滥用可能性的担忧。在这里，我们提出了一个新的调查KOR 使用正电子发射断层扫描（PET），一种脑成像技术， 和放射性配体[11 C]EKAP，其选择性结合脑中的KOR（Aim 1）。鉴于高流行率， BPD中自杀相关行为，我们还将评估KOR可用性、自杀 BPD中的企图史和当前自杀想法（目标2）。最后，我们将评估 冲动性、疼痛耐受性和自伤--BPD的关键内表型，并且对治疗有抵抗力-- 和KOR可用性（目标3）。这项研究的结果将提供潜在的关键洞察的关系 这种新的分子靶点，BPD症状表现和自杀行为之间的联系。根据调查结果，我们 将寻求资金进行更大的PET研究，以测试潜在的非成瘾性KOR靶向药物， 整体BPD症状减轻和自杀风险。