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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要这项研究的目的是研究Kappa阿片受体（KOR）在症状学中的作用边缘人格障碍（BPD），这种疾病与自杀的风险升高有关尝试（最多75％）和自杀死亡（最多10％）。尽管BPD的患病率相对较低（1-5％），但流行病学研究报告说，最近有三分之二的自杀企图发生在 BPD。不幸的是，大多数可用治疗方法无法解决总体BPD症状严重性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症状呈现的网络改变，并与额 - 额 - 边缘电路失调相关联 BPD症状严重程度的增加。研究负责BPD症状的分子机制，特别是自杀风险是促进新疗法发展和促进BPD中的预防风险。新兴的证据意味着Kor在BPD和自杀行为中。 Kor在情感中扮演关键角色调节，社会功能和痛苦感知 - 所有这些都是BPD的核心，并且与自杀有关风险。验尸研究表明，Kor与自杀死亡之间的关联。此外，各种各样的对动物和人类的研究表明，靶向药物可以产生抗抑郁药，抗焦虑，甚至抗自杀性作用。重要的是，KOR代理人对多巴胺的影响相对于滥用药物，减少对滥用潜力的担忧。在这里，我们提出了对Kor的新颖调查使用Polaron发射断层扫描（PET）（一种脑成像技术）的BPD个人的可用性，和放射性[11C] EKAP，它有选择地与大脑中的Kor结合（AIM 1）。考虑到很高的患病率 BPD中与自杀相关的行为，我们还将评估KOR可用性，自杀之间的关联尝试历史和BPD中当前的自杀思想（AIM 2）。最后，我们将评估冲动性，疼痛耐受性和自我伤害 - BPD的关键内表型，并且对治疗有抵抗力 - 和KOR的可用性（AIM 3）。这项研究的结果将为关系提供潜在的至关重要的洞察力在这个新颖的分子靶标，BPD符号表现和自杀行为之间。根据发现我们将为一项更大的宠物研究提供资金，以测试潜在的非添加性KOR针对性药物总体BPD症状减轻和自杀风险。