Endogenous Opioid Modulation by Ketamine

项目摘要 为了开发更好的治疗抑郁症的方法，迫切需要找出关键 推动核心抑郁症状变化的神经化学事件。几个特工最近 已经被证明比传统的抗抑郁药物有更快的效果，这表明 这些新型药物的作用在机械上更接近于那些关键的神经化学事件。 尤其是静脉注射氯胺酮，已被证明在几个小时内起作用，其疗效已被证明 在荟萃分析中得到证实。已发表的工作和初步数据导致了这样的假设 氯胺酮通过显著增强体内的神经传递，改善情绪、兴趣和享乐情绪。 大脑的内源性类阿片系统。拟议中的人类机械学研究将检验这一点。 通过实现两个特定目的提出假说：(1)论证氯胺酮的急性作用 内源性阿片类神经传递；以及(2)确定个体 氯胺酮诱导的MU阿片系统激活的差异与核心的变化有关 抑郁症状。这些目标将使用正电子发射断层扫描和 阿片类药物特异性放射性示踪剂[11C]卡芬太尼在静注氯胺酮治疗抑郁症患者中的应用 这个R21探索性项目有望揭示出，具有神经解剖学和神经化学特异性的 推动人类核心抑郁症状快速变化的一些关键神经事件。 对这种神经化学事件的识别有望催生未来的研究，这些研究将确定 改变Mu-阿片类神经传递对于症状改善是否必要(例如， 通过药物阻断)，以及这些神经变化的逆转或丧失是否是 速效抗抑郁药临床疗效的持久性有限。这项工作将会有积极的意义 通过促进我们对神经事件的理解，这些神经事件是必要和充分的 改善抑郁，使新疗法的设计更加合理。因此，拟议的研究 最终将通过减轻抑郁症的负担来推进NIMH的使命。

Project Summary In order to develop better treatments for depression, there is a critical need to identify the key neurochemical events that drive changes in core depressive symptoms. Several agents have recently been shown to have more rapid effects than conventional antidepressants, suggesting that the sites of action of these novel agents are mechanistically closer to those key neurochemical events. Intravenous ketamine, in particular, has been shown to act within hours, and its efficacy has been confirmed in meta-analyses. Published work and preliminary data have led to the hypothesis that ketamine improves mood, interest, and hedonic tone by acutely enhancing neurotransmission within the brain's endogenous mu-opioid system. The proposed human mechanistic study will test this hypothesis by accomplishing two specific aims: (1) to demonstrate the acute effects of ketamine on endogenous mu-opioid neurotransmission; and (2) to determine the extent to which individual differences in ketamine-induced mu-opioid system activation are associated with changes in core depressive symptoms. These aims will be accomplished using positron emission tomography and the mu-opioid-specific radiotracer [11C]carfentanil in depressed patients receiving intravenous ketamine. This R21 exploratory project is expected to reveal, with neuroanatomical and neurochemical specificity, some of the key neural events that drive rapid changes in core depressive symptoms in humans. Identification of such neurochemical events is expected to spawn future studies that would determine whether changes in mu-opioid neurotransmission are necessary for symptom improvement (e.g., through pharmacological blockade) and whether reversal or loss of those neural changes accounts for the limited durability of the clinical effects of rapidly acting antidepressants. This work will have positive impact by advancing our understanding of those neural events that are necessary and sufficient to ameliorate depression, enabling more rational design of novel therapies. Thus the proposed research will ultimately advance the mission of the NIMH by reducing the burden of depression.