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

• 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
• 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

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”.

项目摘要 酒精使用障碍（AUD）每年花费美国卫生系统2500亿美元，最近 数据表明，美国的饮酒正在上升。有问题的是，只有三种药物获得了FDA批准 为了治疗AUD和不到10％的患者。患者越来越到达 互联网可以找到无需处方的AUD的替代治疗选择。一个相关的例子是 mitrayna speciosa（kratom），一种含阿片类药物的植物，在自我药物慢性疼痛上被外向使用 以及阿片类药物的依赖性。毫不奇怪，鉴于阿片受体系统在酒精使用中的作用 渴望，kratom偶尔被用来自我服药。但是，目前尚未研究 Kratom还是其任何主要的生物碱有效地减少酒精的使用。此外，是否未知 生物碱在酗酒者中具有有益的特性。 kratom包含几个生物碱（包括主要组成型米尔拉氏素），已知与之结合和 激活阿片类药物受体。有趣的是，这些阿片类药物在体外似乎是所谓的“偏见激动剂” 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，但没有与β-art蛋白蛋白相关的途径。我们最近发现G蛋白 靶向δ-阿片受体（ΔOR）的偏置激动剂可以有效地减少小鼠的酒精摄入量。在这个 提案，我们假设Kratom中可以激活Δ的那些生物碱将有助于减少 小鼠的自愿性饮酒，尤其是通过以G蛋白偏见的方式发出信号。我们进一步 假设这些生物碱不会产生条件的地点偏好，这是奖励的量度 药物的特性，通过Δors。为了研究我们的假设 对Δors的强亲和力。然后，我们将评估kratom和这些衍生的阿片类药物是否可以 在野生型小鼠以及在 特定的阿片类受体敲除动物。第三，我们将确定kratom和kratom-在多大程度上 衍生的阿片类药物可以在幼稚和酒精暴露的野生型中引起条件的地点偏好反应 小鼠和ΔOR基因敲除小鼠。 通过该提案成功完成将收集的信息可以开始临床研究 使用Kratom和Kratom衍生的阿片类药物进行AUD治疗以及对公众进行教育 关于Kratom使用的风险和好处。该提案的目的符合我的研究计划的更大目标 这旨在开发新的疗法来治疗AUD。这与主要倡议一致 美国国家酒精滥用和酒精中毒研究所的“为问题提供有效干预措施 在所有年龄段使用”。