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

• 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
• 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

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.

项目摘要 在过去的十年中，阿片类药物的使用在美国急剧上升 阿片类药物依赖性和过量死亡的增加导致了当前的阿片类药物危机。虽然与众不同 已经采取了减少阿片类药物过度利用疼痛管理的措施，诊所中使用阿片类药物的使用仍在继续 导致依赖和过量。在 对非阿片类药物的需求迫切 使用 的 药理 此外，对于大量阿片类药物使用障碍的人 药理疗法以完成阿片类药物的当前治疗方法 紊乱。一个主要的挑战是制定可以减弱有意义方面的新待遇策略 opioids在保留其强大的镇痛特性的同时。 内源性大麻素（ECB）系统是开发新的目标的潜在目标 治疗是基于阿片类药物的疗法的完成。几条证据表明 这 阿片类药物和欧洲央行系统之间的功能相互作用在神经化学的水平上 和分子途径。我们的初步结果发现，间接增强内源性大麻素2-的水平 通过药物抑制其分解代谢酶，单酰基甘油脂肪酶（MAGL），AG水平 衰减吗啡的有益作用，同时保持其镇痛作用。在这个建议中，我们将 在电路，突触和分子水平上剖析2-Ag升高如何减轻阿片类药物的奖励。 最近的研究强调了局部GABA能神经元输入的作用 腹侧换段区域（VTA）中的细分核（RMTG），这是一个关键的多巴胺能脑区域 参与阿片类药物奖励。人们认为阿片类药物可以通过将RMTG抑制作用对VTA多巴胺神经元起作用。 通过激活突触前MU阿片受体（MOR），随后增加了多巴胺细胞的发射和核 驾驶奖励奖励的活动（NAC）活动。但是，对大麻素受体（CB1R）的了解知之甚少 以及这些关键突触处的MORS信号和串扰。 AIM 1将检查VTA中的2-AG机制 Oopioid奖励行为及其对NAC动态的影响。 AIM 2将检查CB1R和MOR在 RMTG→关于阿片类药物奖励行为和NAC动力学的VTA投影。 AIM 3将检查合成和分子 CB1R和MOR串扰的机制，以确定增强2 AG水平如何导致OID钝化 报酬。