Endogenous Opioid Modulation by Ketamine

氯胺酮对内源性阿片类药物的调节

• 批准号: 9344696
• 负责人: Brian James Mickey
• 金额: $ 18.96万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-07 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9344696
• 关键词: Acute; Affect; Anterior; Antidepressive Agents; Attention; Automobile Driving; Brain; Clinical; Data; Development; Dose; Emotions; Event; Future; Globus Pallidus; Glutamate Receptor; Hour; Human; Individual Differences; Infusion procedures; Intravenous; Ketamine; Knowledge; Mediating; Mediator of activation protein; Mental Depression; Mental disorders; Meta-Analysis; Mission; Moods; N-Methylaspartate; National Institute of Mental Health; Opioid; Opioid Analgesics; Opioid Peptide; Pharmaceutical Preparations; Pharmacology; Placebos; Positron-Emission Tomography; Postoperative Period; Pre-Clinical Model; Public Health; Publishing; Randomized; Rattus; Reaction; Receptor Activation; Research; Site; Specificity; Stress; Symptoms; System; Testing; Ventral Striatum; Work; carfentanil; cingulate cortex; clinical effect; depressed patient; depressive symptoms; design; endogenous opioids; hedonic; improved; interest; mood symptom; mu opioid receptors; neurochemistry; neurotransmission; novel; novel therapeutics; preclinical study; radiotracer; receptor binding; relating to nervous system; response; symptomatic improvement

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.

项目摘要 为了开发更好的抑郁症治疗方法，迫切需要确定关键的 导致核心抑郁症状改变的神经化学事件。最近，几名特工 已被证明比传统抗抑郁药具有更快的效果，这表明抑郁症发作的部位 这些新药剂的作用在机制上更接近那些关键的神经化学事件。 特别是静脉注射氯胺酮，已被证明在数小时内起作用，其疗效已被证实。 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， 氯胺酮通过急性增强体内神经传递来改善情绪，兴趣和快感。 大脑的内源性μ阿片系统拟议中的人类机制研究将测试这一点 通过实现两个具体目标：（1）证明氯胺酮的急性作用， 内源性μ-阿片样物质神经传递;和（2）确定个体 氯胺酮诱导的μ-阿片系统激活的差异与核心蛋白的变化有关。 抑郁症状。这些目标将使用正电子发射断层扫描和 μ-阿片特异性放射性示踪剂[11 C]卡芬太尼用于接受氯胺酮静脉注射的抑郁症患者 这个R21探索性项目有望揭示，具有神经解剖学和神经化学特异性， 一些关键的神经事件，驱动人类核心抑郁症状的快速变化。 这种神经化学事件的鉴定有望产生未来的研究， μ-阿片样物质神经传递的变化是否是症状改善所必需的（例如， 通过药理学阻断），以及这些神经变化的逆转或丧失是否解释了 速效抗抑郁药临床效果的持久性有限。这项工作将具有积极意义 通过推进我们对这些神经事件的理解来影响，这些神经事件是必要的和足够的， 改善抑郁症，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。