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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：
10446494
负责人：
Francis Sang Yong Lee
金额：
$ 78.67万
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 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10446494
关键词：
2-arachidonylglycerol Analgesics Animals Arrestins Attenuated Behavior Behavioral Brain Brain region CNR1 gene Calcium Cannabinoids Cell Nucleus Cells Clinic Complement Cultured Cells Dependence Detection Development Disease Dopamine Down-Regulation Electron Microscopy Electrophysiology (science)Endocannabinoids Enzymes Fiber Genetic Heroin Inhibitory Synapse Knock-out Measurement Measures Mediating Molecular Monoacylglycerol Lipases Morphine Mus Neurons Nucleus Accumbens Opiate Addiction Opioid Opioid agonist Optics Overdose Oxycodone Pain management Pathway interactions Persons Pharmaceutical Preparations Pharmacology Photometry Process Property Receptor Signaling Regulation Rewards Role Self Administration Self Stimulation Series Slice Synapses System Testing United States Ventral Tegmental Area attenuation base 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 neurochemistry non-opioid analgesic novel opioid epidemic opioid mortality opioid use opioid use disorder optogenetics preservation presynaptic relating to nervous system tool transmission process treatment strategy

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.

项目总结