Opioidergic alkaloids from Mitragynia Speciosa (kratom) as novel treatment for alcohol use disorder

来自 Mitragynia Speciosa（kratom）的阿片生物碱作为酒精使用障碍的新疗法

基本信息

批准号：
9753100
负责人：
Richard M. van Rijn
金额：
$ 22.2万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753100
关键词：
Address Affect Affinity Age Agonist Alcohol abuse Alcohol consumption Alcohols Alkaloids Behavioral Benefits and Risks Binding Biological Assay C57BL/6 Mouse Cells Cellular Assay Clinical Research Cyclic AMP Data Development Dose Exploratory/Developmental Grant FDA approved Future G-Protein Signaling Pathway G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins General Population Goals Health Personnel Health system Healthcare In Vitro Internet Knockout Mice Measures Medicinal Plants Modeling Mus National Institute on Alcohol Abuse and Alcoholism Nature Neuropharmacology Opiate Addiction Opioid Opioid Receptor Opioid agonist Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Actions Pharmacology Physiological Plants Property Proteins Receptor Signaling Research Research Proposals Rewards Risk Role Running Schedule Signal Transduction System Testing United States Wild Type Mouse addiction alcohol abuse therapy alcohol craving alcohol exposure alcohol use disorder alternative treatment base beta-arrestin chemical binding chronic pain collaborative environment cost drug development drug of abuse effective intervention experimental study high reward high risk kappa opioid receptors knockout animal mu opioid receptors novel novel therapeutics preference problem drinker programs receptor recruit reduced alcohol use response

项目摘要

Project summary Alcohol use disorders (AUD) cost the United States health system roughly $250 billion per year, and recent data suggests that alcohol use in the US is rising. Problematically, only three drugs have been FDA approved for treatment of AUD and less than 10% of patients are prescribed them. Increasingly, patients reach to the internet to find alternative treatment options for AUD without a necessary prescription. A pertinent example is Mitrayna speciosa (kratom), an opioid containing plant that is used extramedically to self-medicate chronic pain as well as opioid dependence. Unsurprisingly given the role of the opioid receptor system in alcohol use and craving, kratom is occasionally used to self-medicate AUD. However, currently no studies have investigated whether kratom or any of its major alkaloids effectively reduce alcohol use. Additionally, it is unknown if these alkaloids have rewarding properties in alcoholics. Kratom contains several alkaloids (including the main constituent mitragynine) that are known to bind to and activate opioid receptors. Interestingly, these opioids appear to act as so-called “biased agonists” in vitro by activating only the G-protein signaling pathway of G protein-coupled receptors (GPCRs), such as the opioid receptor, but not those pathways associated with β-arrestin proteins. We have recently found that G-protein biased agonists targeting δ-opioid receptor (δOR) can effectively reduce alcohol intake in mice. In this proposal, we hypothesize that those alkaloids in kratom that can activate δORs will contribute to reduced voluntary alcohol consumption in mice particularly by signaling in a G-protein biased manner. We further hypothesize that these alkaloids will not produce conditioned place preference, a measure of the rewarding properties of a drug, via δORs. To investigate our hypothesis we will identify six kratom-derived opioids with the strongest affinity for δORs. We will then assess whether kratom and these kratom-derived opioids can reduce alcohol use in a model of limited-access voluntary alcohol consumption in wild-type mice as well as in specific opioid receptor knockout animals. Thirdly, we will determine to what degree kratom and the kratom- derived opioids can induce a conditioned place preference response in naïve and alcohol exposed wild-type mice and in δOR knockout mice. The information that will be gathered by successful completion of this proposal can jumpstart clinical studies into the use of kratom and the kratom-derived opioids for AUD treatment as well as educate the general public about the risks and benefits of kratom use. The aims of this proposal fit the larger goal of my research program which is geared toward development of novel therapeutics to treat AUD. This is in line with the major initiative of the National Institute on Alcohol Abuse and Alcoholism to “offer effective intervention for problem alcohol use at all ages”.

项目概要酒精使用障碍 (AUD) 每年给美国卫生系统造成约 2500 亿美元的损失，最近数据显示，美国的酒精使用量正在上升，但问题是，只有三种药物获得 FDA 批准。仅有不到 10% 的患者接受 AUD 治疗，而且越来越多的患者接受了 AUD 治疗。一个相关的例子是在互联网上寻找 AUD 的替代治疗方案。 Mitrayna spiosa (kratom)，一种含有阿片类药物的植物，可在医学外用于自我治疗慢性疼痛考虑到阿片受体系统在饮酒和饮酒中的作用，这不足为奇。由于渴望，卡痛叶有时会被用来自我治疗 AUD，但目前尚无研究对此进行调查。卡痛叶或其任何主要生物碱是否能有效减少饮酒。此外，尚不清楚这些是否有效。生物碱对酗酒者有有益的作用。卡痛含有多种生物碱（包括主要成分帽柱木碱），已知这些生物碱可以结合并象征性地激活阿片受体，这些阿片类药物似乎在体外充当所谓的“偏向激动剂”。仅激活 G 蛋白偶联受体 (GPCR) 的 G 蛋白信号通路，例如阿片类药物受体，但不是那些与 β-arrestin 蛋白相关的途径。我们最近发现了 G 蛋白。针对δ-阿片受体（δOR）的偏向激动剂可以有效减少小鼠的酒精摄入量。根据建议，我们认为卡痛叶中那些可以激活 δOR 的生物碱将有助于减少小鼠自愿饮酒，特别是通过 G 蛋白偏向方式发出信号。培养这些生物碱不会产生条件性位置偏好，这是衡量奖励的措施为了研究我们的假设，我们将鉴定六种卡痛叶衍生的阿片类药物。然后我们将评估卡痛叶和这些卡痛叶衍生的阿片类药物是否可以发挥对 δOR 的最强亲和力。在野生型小鼠的有限自愿饮酒模型以及第三，我们将确定卡痛叶和卡痛叶的程度。衍生的阿片类药物可以在幼稚和酒精暴露的野生型中诱导条件性位置偏好反应小鼠和 δOR 敲除小鼠。成功完成该提案所收集的信息可以快速启动临床研究使用卡痛叶和卡痛叶衍生的阿片类药物进行 AUD 治疗并对公众进行教育关于卡痛叶使用的风险和益处该提案的目的符合我的研究计划的更大目标。旨在开发治疗 AUD 的新疗法，这与该重大举措是一致的。国家酒精滥用和酒精中毒研究所“为问题酒精提供有效干预适合所有年龄段使用”。