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

摘要 阿片类药物已被广泛用于控制医疗和手术疼痛，但阿片类药物的使用 疾病（OUD）已经成为严重的、普遍的和昂贵的公共卫生问题。确定风险因素 处方阿片类药物使用后OUD的发展可能有助于减少严重损伤和死亡相关的 结果，如过量。基于海马神经回路的语境加工是一种重要的神经认知加工机制， 与OUD相关的进程。背景处理缺陷的证据见于精神病、物质使用、 和慢性疼痛人群。成人OUD的一个主要预测因素也与上下文处理有关， 不良童年经历（ACE）。ACE预示着高OUD率，并与复杂的CO2相关。 发病率（例如，慢性疼痛、精神疾病、其他物质使用障碍），使治疗复杂化 对于OUD。ACE还通过应激激素对HPC神经元的有害作用损害HPC功能。 因此，ACE可能导致HPC回路功能障碍和上下文处理缺陷，提供了一个共享的途径， 慢性疼痛、处方阿片类药物使用和OUD发展。Katz R 01将利用PI的专业知识， 创伤的神经认知机制，以提供对风险机制途径的首次直接检查 OUD涉及ACE和上下文处理缺陷之间的联系。我们将检查75名成年人， OUD服用处方阿片激动剂丁丙诺啡（BUP），并将其与两个对照组进行比较：75 成人没有OUD服用BUP和75成人没有OUD和不服用BUP，在一项横断面研究。我们 将使用一个经过验证的上下文处理范式来询问HPC的结构和功能以及行为 性能阿片类药物滥用、OUD和ACE的经验证的自我报告和客观指标将用于 检查ACE、上下文处理和OUD之间的链接。我们的具体目标包括：1）识别HPC- OUD中基于回路的上下文处理缺陷，独立于阿片激动剂效应; 2）建立 ACE、上下文处理和OUD严重程度之间的联系;以及3）探索常见症状 域与ACE、上下文处理和OUD相关联。该项目的研究结果将导致 纵向工作的潜力，以跟踪一个机制的途径，有助于解释共病之间 慢性疼痛、应激相关疾病和处方阿片类药物使用后OUD的发展。这可最终 为发现预防和治疗范例打开了新的大门，这些范例将在阿片类药物使用时识别那些处于风险中的人。 （高ACE，不良的上下文处理），并最终塑造神经科学知情的方式， 即使在功能缺陷发展之后也要进行补救。

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.