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 阿片类药物在努力控制内科和外科疼痛方面得到了广泛的处方，但阿片类药物的使用 失序已成为一个严重、普遍且代价高昂的公共卫生问题。确定以下风险因素 在处方阿片类药物使用后发生OUD有助于减少与严重伤害和死亡相关的事件。 结果，比如服药过量。海马(HPC)-基于回路的语境处理是一种重要的神经认知 与OUD关联的进程。背景加工缺陷的证据在精神病学、药物使用、 和慢性疼痛人群。成人OUD的一个主要预测因素也与语境加工有关 不良童年经历(A级)。ACE预测较高的OUD速率，并与复杂的 使治疗复杂化的发病率(如慢性疼痛、精神疾病、其他物质使用障碍) 为了奥德。ACE还通过应激激素对HPC神经元的有害影响来损害HPC的功能。 因此，ACE可能导致HPC电路功能障碍和上下文处理缺陷，从而提供共享路径 慢性疼痛，处方阿片类药物的使用和OUD的发展。这款Katz R01将利用PI的专业知识 创伤的神经认知机制提供了对风险机制的第一次直接检查 对于OUD来说，这涉及到ACE和上下文处理缺陷之间的联系。我们将检查75名患有 服用处方阿片激动剂丁丙诺啡(BUP)，并与两个对照组进行比较：75 在一项横断面研究中，没有服用BUD的成年人和75名没有服用BUD和不服用BUP的成年人。我们 将使用经过充分验证的环境处理范例来询问HPC的结构和功能以及行为 性能。将使用经过验证的自我报告和阿片类药物滥用、OUD和ACE的客观措施来 检查ACE、情景处理和OUD之间的链接。我们的具体目标包括：1)识别高性能混凝土- OUD中基于电路的语境加工缺陷，与阿片类激动剂效应无关；2)建立 ACE、情景处理和OUD严重性之间的联系；以及3)了解常见症状 域与ACE、环境处理和OUD相关联。这个项目的发现将导致 以追踪一条机械途径的可能性来进行纵向研究，以帮助解释 慢性疼痛，应激相关障碍，以及处方阿片类药物使用后出现的不良反应。这最终可能会 为发现预防和治疗模式打开新的大门，这些模式将在阿片类药物出现时识别风险人群 是规定的(高A，糟糕的上下文处理)，并最终形成神经科学知情的方式 即使功能缺陷已经形成，也要加以补救。

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.