Circuit and Synaptic Mechanisms of Endocannabinoid-Opioid Crosstalk

项目摘要 在过去的十年里，阿片类药物的使用在美国急剧上升， 阿片类药物依赖和过量死亡的增加导致了目前的阿片类药物危机。虽然不同 已采取措施减少阿片类药物在疼痛管理中的过度使用，诊所中阿片类药物的使用仍在继续 导致依赖和过量在 迫切需要非阿片类药物 使用 的 药理 此外，对于大量患有阿片类药物使用障碍的人， 补充阿片类药物当前治疗的药物疗法 disorder.一个主要的挑战是开发新的治疗策略，可以削弱奖励方面 阿片类药物，同时保持其强大的镇痛性能。 内源性大麻素（eCB）系统是开发新的 作为阿片类药物治疗的补充。一些证据表明 的 阿片类药物和eCB系统在神经化学、神经解剖学水平上的功能相互作用 和分子途径。我们的初步结果发现，间接提高内源性大麻素2- AG水平通过药理学抑制其分解代谢酶，单酰基甘油脂肪酶（MAGL）， 减弱吗啡的奖赏作用，同时保持其镇痛作用。在本提案中，我们将 在回路、突触和分子水平上剖析升高的2-AG如何减弱阿片类物质的奖赏。 最近的研究强调了来自吻内侧核的局部GABA能神经元输入的作用， 被盖核（RMTg）在调节腹侧被盖区（VTA）中的作用，腹侧被盖区是多巴胺能的关键脑区 参与阿片类药物的奖励阿片类药物被认为是通过解除RMTg对腹侧被盖区多巴胺神经元的抑制作用而起作用的 通过激活突触前μ阿片受体（莫尔），随后增加多巴胺细胞放电和核 NAc：驱动奖励的活动。然而，关于大麻素受体（CB 1 R） MORs在这些关键突触上发出信号并相互干扰。目的1将研究2-AG机制在腹侧被盖区 阿片奖赏行为及其对NAc动力学的影响。目的2将检查CB 1 R和莫尔在 RMTg→VTA投射对阿片类药物奖赏行为和NAc动力学的影响目标3将检查突触和分子 CB 1 R和莫尔串扰的机制，以确定2-AG水平的提高如何导致阿片样物质的钝化 奖励

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.