A mechanistic investigation of risk factors for opioid use disorder: Examining hippocampal-based context-dependent learning and memory associated with adverse childhood experiences

阿片类药物使用障碍危险因素的机制研究：检查与不良童年经历相关的基于海马的情境依赖学习和记忆

• 批准号: 10707793
• 负责人: Elizabeth Duval
• 金额: $ 70.79万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707793
• 关键词: Adult; Amygdaloid structure; Animals; Anxiety; Behavioral; Brain; Buprenorphine; Cessation of life; Chronic Disease; Clinical; Cognitive; Complex; Control Groups; Cross-Sectional Studies; Cues; Dangerousness; Detection; Development; Disparate; Emotional; Foundations; Functional disorder; Future; Hippocampus; Hormones; Individual; Injury; Investigation; Learning; Link; Longitudinal Studies; Measures; Medical; Memory; Mental Depression; Mental disorders; Modeling; Modernization; Neurocognitive; Neurocognitive Deficit; Neurons; Neurosciences; Opioid agonist; Outcome; Overdose; Pain Disorder; Panthera leo; Pathway interactions; Patient Self-Report; Patients; Performance; Persons; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prevention; Process; Public Health; Rewards; Risk; Risk Factors; Sampling; Severities; Shapes; Stress; Structure; Substance Use Disorder; Testing; Trauma; Work; adverse childhood events; anxiety symptoms; associated symptom; brain based; chronic pain; common symptom; comorbidity; conditioned fear; cost; depressive symptoms; design; disorder risk; emotional functioning; experience; mortality; neural; opioid epidemic; opioid misuse; opioid overdose; opioid use; opioid use disorder; prescription opioid; programs; psychiatric symptom; recruit; remediation; risk sharing; stress related disorder; substance use; surgical pain; tool; way finding

Abstract Opioid medications have been widely prescribed in efforts to control medical and surgical pain, but opioid use disorder (OUD) has become a serious, prevalent, and costly public health problem. Identifying risk factors for the development of OUD after prescribed opioid use could help reduce serious injury and mortality-related outcomes, like overdose. Hippocampal (Hpc)-circuit based context processing is an important neuro-cognitive process associated with OUD. Evidence for context processing deficits is seen in psychiatric, substance use, and chronic pain populations. One major predictor of adult OUD that is also linked to context processing is adverse childhood experiences (ACEs). ACEs predict high OUD rates and are associated with complex co- morbidity (e.g., chronic pain, psychiatric conditions, other substance use disorders) that complicates treatment for OUD. ACEs also compromise Hpc function through detrimental effects of stress hormones on Hpc neurons. Thus, ACEs may lead to Hpc circuitry dysfunction and context processing deficits, providing a shared pathway to chronic pain, prescribed opioid use, and OUD development. This Katz R01 will utilize the PI’s expertise in neurocognitive mechanisms of trauma to provide the first direct examination of a mechanistic pathway of risk for OUD that involves links between ACEs and context processing deficits. We will examine 75 adults with OUD taking the prescription opioid agonist buprenorphine (BUP) and compare them to two control groups: 75 adults without OUD taking BUP and 75 adults without OUD and not taking BUP, in a cross-sectional study. We will use a well-validated context processing paradigm to interrogate Hpc structure and function and behavioral performance. Validated self-report and objective measures of opioid misuse, OUD, and ACEs will be used to examine links between ACEs, context processing, and OUD. Our specific aims include: 1) identifying Hpc- circuit based context processing deficits in OUD, independent of opioid agonist effects; 2) establishing links between ACEs, context processing, and OUD severity; and 3) exploring how common symptom domains are associated with ACEs, context processing, and OUD. The findings from this project will lead to longitudinal work with the potential to trace a mechanistic pathway that helps explain co-morbidities between chronic pain, stress-related disorders, and OUD development after prescribed opioid use. This may ultimately open new doors to discovery of prevention and treatment paradigms that will identify those at risk when opioids are prescribed (high ACEs, poor context processing), and ultimately shape neuroscience-informed ways to remediate functional deficits even after they have developed.

抽象的 阿片类药物已被广泛规定以控制医学和手术疼痛，但使用阿片类药物 疾病（OUD）已成为严重，普遍且昂贵的公共卫生问题。确定风险因素 开处方使用阿片类药物后的OUD的发展可能有助于减少严重的伤害和死亡率有关 结果，例如过量。海马（HPC）基于电路的上下文处理是重要的神经认知 与Oud相关的过程。上下文处理缺陷的证据在精神病，使用物质中可以看出 和慢性疼痛人群。与上下文处理有关的成人OUD的一个主要预测指标是 不利的童年经历（ACE）。 ACE可以预测高速率，并与复杂的共同共同 发病率（例如，慢性疼痛，精神病，其他物质使用障碍）使治疗复杂化 对于Oud。 ACE还通过应力角对HPC神经元的有害影响损害了HPC功能。 这可能会导致HPC电路功能障碍和上下文处理防御措施，提供共享途径 慢性疼痛，处方阿片类药物的使用和OUD发育。这个Katz R01将利用Pi的专业知识 创伤的神经认知机制，以首次直接检查风险的机械途径 对于涉及ACE和上下文处理缺陷之间的链接的OUD。我们将检查75名成年人 OUD服用处方阿片类动力学丁丙诺啡（BUP），并将它们与两个对照组进行比较：75 在一项横断面的研究中，没有Oud的成年人，没有OUD和75名没有OUD且不服用BUP的成年人。我们 将使用验证良好的上下文处理范例来询问HPC结构，功能和行为 表现。经过验证的自我报告和阿片类遗物，OUD和ACE的客观度量将用于 检查ACE，上下文处理和OUD之间的链接。我们的具体目的包括：1）确定HPC- 基于电路的上下文处理防御源，与阿片类药物激动剂效应无关； 2）建立 ACE，上下文处理和OUD严重性之间的联系； 3）探索常见症状 域与ACE，上下文处理和OUD相关联。该项目的发现将领导 进行纵向工作，以追踪有助于解释合并症的机械途径的潜力 处方使用阿片类药物后，慢性疼痛，与压力相关的疾病和OUD发育。这可能最终 打开发现预防和治疗范式的新门，这些范例将确定阿片类药物时有危险的人 开处方（高昂的王牌，不良的上下文处理），并最终塑造神经科学知识的方法 补救功能缺陷即使在开发之后。