Endocannabinoid System Alterations in Opioid Use Disorder (OUD)

阿片类药物使用障碍 (OUD) 中的内源性大麻素系统改变

• 批准号: 10303918
• 负责人: Anahita Bassir Nia
• 金额: $ 20.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303918
• 关键词: 2-arachidonylglycerol; Age; Agonist; Animal Model; Animals; Attention; Attenuated; Blood; Blood specimen; Brain imaging; Brain region; CNR1 gene; Cannabinoids; Cerebral cortex; Chronic; Clinical Research; Clinical Trials; Collaborations; DSM-V; Data; Development; Diagnosis; Dopamine; Dose; Down-Regulation; Drug usage; Endocannabinoids; Enhancers; Enzymes; Ethnic Origin; Exposure to; FAAH inhibitor; Feasibility Studies; Gender; Goals; Hippocampus (Brain); Human; Individual; Ligands; Literature; Measurement; Measures; Methadone; Methods; Midbrain structure; Monitor; Monoacylglycerol Lipases; Neurons; Nicotine; Nucleus Accumbens; Opiate Addiction; Opioid; Peripheral; Pharmaceutical Preparations; Pharmacology; Plasma; Positron-Emission Tomography; Psychoses; Race; Reporting; Research; Resolution; Rewards; Sampling; Serum; System; Therapeutic; Time; Universities; Up-Regulation; Withdrawal Symptom; anandamide; endogenous cannabinoid system; endogenous opioids; fatty acid amide hydrolase; imaging study; in vivo; interest; liquid chromatography mass spectrometry; marijuana use disorder; methadone treatment; mu opioid receptors; mu receptors; novel; novel strategies; opioid epidemic; opioid use; opioid use disorder; opioid withdrawal; pre-clinical; receptor expression; repository; tomography

ABSTRACT There are close interactions between the endogenous opioid system and endocannabinoid (eCB) system, which result in stronger reinforcing/rewarding effects of both opioids and cannabinoids. Targeting the eCB system has attracted great attention in the treatment of opioid use disorder (OUD), particularly given the urgent need to curb the current opioid crisis in the US. Increasing lines of evidence from animal studies demonstrate that chronic opioid use suppresses the eCB system. In particular, animal studies of chronic opioid administration reported decreased cannabinoid receptor type 1 (CB1R) in cortex. However, CB1R availability has not yet been investigated in humans with OUD. The availability of a PET ligand for CB1R makes it possible to study CB1R availability in individuals with OUD in vivo for the first time. The aim of this proposal is to use the CB1R-specific ligand [11C]OMAR and High Resolution Research Tomography (HRRT), a PET scanner with the highest sensitivity and resolution available for human brain imaging, to measure CB1R availability in vivo in individuals with OUD. As an exploratory aim, we will also measure peripheral levels of the eCBs anandamide (AEA) and 2-arachidonoylglycerol (2-AG) using liquid chromatography–mass spectrometry (LC-MS). Methods: Otherwise healthy individuals with opioid use disorder (on stable dose of maintenance methadone) and age-, gender-, race/ethnicity-matched healthy controls without recent use of any drugs (except nicotine, which will be matched between two groups) will undergo a single PET scan with [11C]OMAR and blood sampling to measure serum eCB levels (AEA and 2-AG). Hypotheses: Consistent with animal studies, relative to healthy controls, individuals with OUD will have lower availability of CB1R in cerebral cortex. Pilot data: Individuals with OUD (n=2) showed 12.76% lower cortical CB1R availability compared to matched historical controls from our repository of [11C]OMAR PET studies.

抽象的 内源性阿片类药物系统与内丙诺巴素（ECB）系统之间存在密切的相互作用， 这会导致阿片类药物和大麻素的更强大的增强/奖励作用。针对欧洲央行 系统引起了阿片类药物使用障碍（OUD）的极大关注，特别是考虑到紧急情况 需要遏制美国当前的阿片类药物危机。越来越多的动物研究证据表明 这种慢性阿片类药物使用抑制了欧洲央行系统。特别是慢性阿片类动物研究 给药报道，皮质中的1型大麻素受体（CB1R）降低。但是，CB1R可用性 尚未在人类中对Oud进行调查。 CB1R的宠物配体的可用性使得它可能 首次研究了OUD IN VIVO的个体的CB1R可用性。 该建议的目的是使用CB1R特异性配体[11C] OMAR和高分辨率研究 断层扫描（HRRT），一种具有最高灵敏度和分辨率的PET扫描仪 成像，测量OUD个体体内的CB1R可用性。作为探索目的，我们也将 使用液体测量ECB Anandamide（AEA）（AEA）和2-芳基烯丙基甘油（2-AG）的外围水平 色谱 - 质谱（LC-MS）。 方法：否则健康的患有阿片类药物使用障碍的人（关于稳定的维护方法adone剂量） 以及年龄，性别，种族/种族匹配的健康对照，没有最近使用任何药物（尼古丁除外， 将在两组之间匹配）将接受[11C] Omar和Blood的单个PET扫描 抽样以测量血清欧洲央行水平（AEA和2-AG）。 假设：与动物研究一致，相对于健康对照，OUD的个体将较低 CB1R在大脑皮层中的可用性。 试点数据：与匹配相比，带有OUD（n = 2）的个体（n = 2）的皮质CB1R可用性降低了12.76％ 我们[11C] Omar Pet研究存储库的历史控制。