Circuit and Synaptic Mechanisms of Endocannabinoid-Opioid Crosstalk

内源性大麻素-阿片类药物串扰的回路和突触机制

基本信息

批准号：
10709494
负责人：
Francis Sang Yong Lee
金额：
$ 37.03万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10709494
关键词：
2-arachidonylglycerol Analgesics Animals Arrestins Attenuated Behavior Behavioral Brain Brain region Calcium Cannabinoids Cell Nucleus Cells Clinic Complement Cultured Cells Dependence Detection Development Disease Disinhibition Dopamine Down-Regulation Electron Microscopy Electrophysiology (science)Endocannabinoids Enzymes Fiber Genetic Heroin Inhibitory Synapse Knock-out Measurement Measures Mediating Molecular Monoacylglycerol Lipases Morphine Mus Neuroanatomy Neurons Nucleus Accumbens Opiate Addiction Opioid Opioid agonist Optics Overdose Oxycodone Pain management Pathway interactions Persons Pharmaceutical Preparations Photometry Process Property Receptor Cross-Talk Receptor Signaling Regulation Rewards Role Self Administration Self Stimulation Series Slice Synapses System Testing United States Ventral Tegmental Area attenuation behavior measurement cannabinoid receptor cellular imaging conditioned place preference desensitization dopaminergic neuron drug seeking behavior endocannabinoid signaling endogenous cannabinoid system in vivo male mu opioid receptors neural neurochemistry non-opioid analgesic novel novel therapeutic intervention opioid epidemic opioid mortality opioid use opioid use disorder optogenetics pharmacologic preservation presynaptic reinforced behavior tool transmission process

项目摘要

Project Summary For the past decade, the use of opioids has risen dramatically in the United States and the disproportional increase in opioid dependence and overdose death has led to the current opioid crisis. Although different measures have been taken to reduce opioid overutilization for pain management, opioid use in clinics continues leading to dependence and overdose. In there is a compelling need for non-opioid use of pharmacological addition, for the significant number of people with opioid use disorder, pharmacological therapies to complement current treatments for opioid disorder. A major challenge is to develop new treatment strategies that can attenuate the rewarding aspects opioids while preserving their powerful analgesic properties. endocannabinoid (eCB) system serves as a potential target for the development of new treatments as a complement to opioid based treatments. Several lines of evidence suggest The functional interaction between the opioid and the eCB system at the level of neurochemical, neuroanatomical and molecular pathways. Our preliminary results find that indirectly enhancing levels of the endocannabinoid 2- AG levels through pharmacological inhibition of its catabolic enzyme, monoacylglycerol lipase (MAGL), attenuates the rewarding effects of morphine, while maintaining its analgesic effects. In this proposal we will dissect at a circuit, synaptic and molecular level how elevated 2-AG attenuates opioid reward. Recent studies have underscored the role of local GABAergic neuronal inputs from the rostromedial tegmental nucleus (RMTg) in regulating the ventral tegmental area (VTA), a key dopaminergic brain region involved in opioid reward. Opioids are thought to act by disinhibiting RMTg inhibition onto VTA dopamine neurons by activating presynaptic mu opioid receptors (MOR), subsequently increasing dopamine cell firing and nucleus accumbens (NAc) activity that drives reward. However, little is known about how cannabinoid receptors (CB1R) and MORs signal and crosstalk at these key synapses. Aim 1 will examine 2-AG mechanisms in the VTA on opioid reward behavior and its effect on NAc dynamics. Aim 2 will examine the role of CB1R and MOR in the RMTg→VTA projection on opioid reward behavior and NAc dynamics. Aim 3 will examine synaptic and molecular mechanisms of CB1R and MOR crosstalk to determine how enhancing 2-AG levels leads to blunted opioid reward.

项目概要在过去的十年中，阿片类药物的使用在美国急剧增加，并且不成比例阿片类药物依赖的增加和过量死亡导致了当前的阿片类药物危机，尽管情况不同。已采取措施减少阿片类药物在疼痛治疗中的过度使用，阿片类药物在诊所的使用仍在继续导致依赖性和过量。迫切需要非阿片类药物使用的药理学的此外，对于大量患有阿片类药物使用障碍的人来说，补充当前阿片类药物治疗的药物疗法一个主要的挑战是开发新的治疗策略，以减弱有益的方面。阿片类药物，同时保留其强大的镇痛特性。内源性大麻素（ECB）系统是开发新药物的潜在目标多项证据表明，治疗是阿片类药物治疗的补充。这阿片类药物与 eCB 系统在神经化学、神经解剖学水平上的功能相互作用我们的初步结果发现，间接提高内源性大麻素 2- 的水平。 AG 水平通过其分解代谢酶、单酰基甘油脂肪酶 (MAGL) 的药理学抑制，减弱吗啡的奖励作用，同时保持其镇痛作用。在电路、突触和分子水平上剖析升高的 2-AG 如何减弱阿片类药物的奖赏。最近的研究强调了来自嘴内侧局部 GABA 能神经输入的作用被盖核（RMTg）调节腹侧被盖区（VTA），这是一个关键的多巴胺能大脑区域阿片类药物被认为是通过解除对 VTA 多巴胺神经元的 RMTg 抑制来发挥作用。通过激活突触前 mu 阿片受体 (MOR)，随后增加多巴胺细胞放电和细胞核然而，人们对大麻素受体（CB1R）如何驱动奖励知之甚少。目标 1 将检查 VTA 中的 2-AG 机制。阿片类药物奖赏行为及其对 NAc 动力学的影响目标 2 将研究 CB1R 和 MOR 在 NAc 动力学中的作用。 RMTg→VTA 对阿片类药物奖励行为和 NAc 动力学的预测将检查突触和分子。 CB1R 和 MOR 串扰机制，以确定增强 2-AG 水平如何导致阿片类药物减弱报酬。