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

项目摘要 酒精使用障碍（AUD）每年花费美国卫生系统大约2500亿美元，最近 数据显示，美国的饮酒量正在上升。有问题的是，只有三种药物被FDA批准 用于治疗AUD，不到10%的患者接受处方。越来越多的病人， 在没有必要处方的情况下，通过互联网寻找AUD的替代治疗方案。一个相关的例子是 Mitrayna speciosa（kratom），一种含有阿片类药物的植物，用于治疗慢性疼痛 以及阿片类药物依赖。考虑到阿片受体系统在酒精使用中的作用， 渴望，kratom偶尔会用来自我安慰AUD。然而，目前还没有研究调查 kratom或其任何主要生物碱是否有效地减少酒精使用。此外，尚不清楚这些 生物碱在酗酒者中具有有益的特性。 Kratom含有几种生物碱（包括主要成分mitragynine），已知其与 激活阿片受体有趣的是，这些阿片类药物似乎在体外作为所谓的“偏向性激动剂”， 仅激活G蛋白偶联受体（GPCR）的G蛋白信号传导途径，例如阿片样物质 受体，但不是与β-arrestin蛋白相关的那些途径。我们最近发现G蛋白 δ-阿片受体（δOR）偏向性激动剂能有效地减少小鼠的酒精摄入。在这 我们假设，kratom中那些可以激活δ OR的生物碱将有助于减少 自愿饮酒的小鼠，特别是通过信号在G蛋白偏向的方式。我们进一步 我假设这些生物碱不会产生条件性位置偏好，这是一种衡量奖励的方法。 药物的性质，通过δ OR。为了研究我们的假设，我们将确定六种Kratom衍生的阿片类药物， 对δ OR的亲和力最强。然后，我们将评估kratom和这些kratom衍生的阿片类药物是否可以 在野生型小鼠有限自愿饮酒模型中减少酒精使用， 特定阿片受体敲除动物。第三，我们将确定在何种程度上kratom和kratom- 衍生的阿片类药物可以诱导幼稚和酒精暴露的野生型条件性位置偏爱反应， 小鼠和δOR敲除小鼠中。 成功完成本提案所收集的信息可以启动临床研究 使用kratom和kratom衍生的阿片类药物治疗AUD，并教育公众 关于使用kratom的风险和好处。这个建议的目的符合我的研究计划的更大目标 其旨在开发治疗AUD的新疗法。这符合重大举措 国家酒精滥用和酒精中毒研究所的一项研究，旨在“为问题酒精提供有效的干预措施 在所有年龄使用”。

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”.