Endocannabinoid System Alterations in Opioid Use Disorder (OUD)

摘要 内源性阿片系统和内源性大麻素系统之间存在密切的相互作用， 这导致阿片类物质和大麻素两者的更强的增强/奖励作用。针对eCB 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，特别是考虑到迫切需要 我们需要遏制美国目前的阿片类药物危机。越来越多的动物研究证据表明， 长期使用阿片类药物会抑制eCB系统特别是，慢性阿片类药物的动物研究 施用后，报告皮质中大麻素受体1型（CB 1 R）减少。然而，CB 1 R的可用性 尚未在OUD患者中进行研究。CB 1 R的PET配体的可用性使得有可能 研究CB 1 R在OUD患者体内的可用性。 本提案的目的是使用CB 1 R特异性配体[11 C]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，可用于人脑 成像，以测量OUD个体体内CB 1 R的可用性。作为一个探索性的目标，我们还将 使用液体培养基测量eCB花生四烯酸酰胺（AEA）和2-花生四烯酸甘油（2-AG）的外周水平 色谱-质谱法（LC-MS）。 方法：其他健康的阿片类药物使用障碍个体（稳定剂量的美沙酮维持治疗） 和年龄、性别、种族/民族匹配的健康对照，近期未使用任何药物（尼古丁除外， 将在两组之间进行匹配）将接受单次PET扫描（使用[11 C]OMAR和血液 采样以测量血清eCB水平（AEA和2-AG）。 假设：与动物研究一致，相对于健康对照组，OUD个体将具有较低的 CB 1 R在大脑皮层中的可用性。 初步数据：OUD患者（n=2）的皮质CB 1 R可用性比匹配患者低12.76%。 来自我们的[11 C]OMAR PET研究库的历史对照。

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.