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，不成比例的 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。尽管不同 已采取措施减少阿片类药物在疼痛控制中的过度使用，临床上阿片类药物的使用仍在继续 导致依赖和过量用药。在……里面 迫切需要非阿片类药物 使用 的 药理作用 此外，对于相当数量的阿片类药物使用障碍患者来说， 药物治疗对阿片类药物现有治疗的补充 无序。一个主要的挑战是开发新的治疗策略，以减弱有回报的方面 阿片类药物，同时保留其强大的止痛特性。 内源性大麻素(ECB)系统是开发新的潜在靶点 作为基于阿片类药物的治疗的补充。有几行证据表明 这个 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 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- 通过药物抑制其分解代谢酶单酰甘油脂肪酶(MAGL)， 减弱吗啡的奖赏作用，同时保持其止痛作用。在本提案中，我们将 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励。 最近的研究强调了来自旋转内侧的局部GABA能神经元输入的作用 被盖核(RMTg)对多巴胺能脑区腹侧被盖区(VTA)的调节作用 参与阿片类药物奖励。阿片类药物被认为是通过解除对VTA多巴胺神经元的RMTg抑制而发挥作用的 通过激活突触前MU阿片受体(MOR)，随后增加多巴胺细胞的放电和核团 伏隔核(NAC)活动，驱动奖励。然而，关于大麻素受体(CB1R)如何 而MORS在这些关键突触处发出信号并进行串扰。目标1将研究VTA中的2-AG机制 阿片类奖赏行为及其对NAC动态的影响。目标2将研究CB1R和MOR在 RMTG→VTA对阿片类药物奖赏行为和NAC动态的预测。目标3将检查突触和分子 CB1R和MOR串扰确定2-AG水平升高如何导致阿片类药物钝化的机制 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.