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，以控制医疗和手术疼痛，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。 开处方使用阿片类药物后的OUD的发展可以帮助减少严重的伤害，并与死亡率相关 结局，例如过量的海马（HPC） - 基于电路的上下文处理是一个重要的神经认知 与OUD相关的过程。 和慢性疼痛人群。 不良的儿童经验（ACE）。 发病率（例如慢性疼痛，精神病，其他药物使用障碍）使治疗复杂化 对于ACES。 因此，ACE可能导致HPC电路功能障碍和上下文处理缺陷，提供共享途径 为了慢性疼痛，处方阿片类药物的使用和OUD开发。 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。 Oud服用Prestiid agonid激动剂丁丙诺啡（BUP），并将它们与两个对照组进行比较：75 在一项跨识别研究中，没有OUD的成年人和75名成年人，没有bup 将使用良好的磁盘上下文处理范例来询问HPC结构和功能和行为 绩效。 检查ACE，上下文处理和OUD之间的链接。 基于电路的上下文处理缺陷，独立性的Agonid agonidts; 2）建立 ACE，上下文处理和OUD严重性之间的联系； 域与ACE，上下文处理和OUD相关联。 纵向工作，有潜力 慢性疼痛，与压力相关的疾病和处方阿片类药物后的发育可能最终 为发现预防和治疗范式发现的新大门，然后识别阿片类药物 开处方（高级王牌，上下文处理差）和最终形状神经科学知识的方法 补救功能缺陷即使在开发后也是如此。