Endocannabinoid System Alterations in Opioid Use Disorder (OUD)

摘要 内源性阿片系统和内源性大麻(ECB)系统之间存在密切的相互作用， 这导致阿片类药物和大麻类药物具有更强的强化/奖励作用。把目标对准欧洲央行 系统在阿片类药物使用障碍(OUD)的治疗中引起了极大的关注，特别是在紧急情况下 需要遏制目前美国的阿片类药物危机。越来越多的动物研究证据表明 长期使用阿片类药物抑制了欧洲央行的体系。特别是，慢性阿片类药物的动物研究 药物管理局报告皮质中大麻素受体1型(CB1R)减少。然而，CB1R的可用性 尚未在患有OUD的人类中进行研究。用于CB1R的PET配体的可用性使其成为可能 首次在活体内研究CB1R在OUD患者中的可用性。 该提案的目的是使用CB1R特异性配体[11C]Omar和高分辨率研究 断层扫描(HRRT)，一种可用于人脑的最高灵敏度和分辨率的PET扫描仪 成像，以测量CB1R在OUD患者体内的可用性。作为一个探索性目标，我们还将 用液体测定外周血中ECBS花生胺(AEA)和2-花生四烯基甘油(2-AG)的水平 色质联用(LC-MS)。 方法：其他健康的阿片类药物使用障碍患者(服用稳定剂量的维持性美沙酮) 年龄、性别、种族/民族匹配的健康对照组，最近没有使用任何药物(尼古丁除外， 将在两组之间匹配)将接受用[11C]Omar和血液进行的单次PET扫描 取样测量血清ECB水平(AEA和2-AG)。 假说：与动物研究相一致，相对于健康对照组，患有OUD的个体将会有更低的 CB1R在大脑皮层的可用性。 试验数据：与匹配的人相比，患有OUD(n=2)的人皮质CB1R利用率降低12.76% 来自我们的[11C]Omar PET研究的历史对照。

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.