Therapeutic secrets of kratom alkaloid mitragynine: Testing efficacy in preclinical neuropathic pain and abuse liability models and characterization of underlying opioid and adrenergic mechanisms

项目摘要 Kratom，也被称为Mitragyna speciosa，是咖啡家族中一种有争议的植物， 20生物碱，其中几个是生物活性，与mitragynine是最普遍的。Kratom有一个 迷人的，混合的，药理学特征，结合阿片类药物和兴奋剂的作用，与兴奋剂 在低至中等剂量下最常见的效应，在较高剂量下出现阿片样物质效应。 虽然kratom在东南亚已经使用了几个世纪来对抗疲劳和管理疼痛，但阿片类药物 戒断，发烧和抑郁症，它在美国的使用增加，最近一直是一个主题， FDA公共卫生咨询，解决与其使用相关的不良风险和滥用责任。不幸的是， 关于kratom药理学的大多数信息都是从人类用户那里获得的。的 科学家，临床医生和政府官员面临的关于kratom潜在调度的决定 由于缺乏从实验室获得的临床前实验数据， 动物虽然kratom的成瘾特性引起了公众的最大关注，但这可能是由于 μ阿片受体激活，这是kratom的兴奋作用，可能是由于增强肾上腺素能 传播，特别是研究不足，也许最相关的治疗潜力。我们的目标 在这个R21申请是提供kratom生物碱（mitragynine）的第一次全面研究， 神经性疼痛和自我给药（SA）的临床前模型，并定义和区分， 在受体机制和作用位点方面，mitragynine的神经保护和增强功效。 使用大鼠测试的总体假设是，mitragynine减少化疗诱导的神经病理性 疼痛通过增强α2-肾上腺素受体的肾上腺素能传递，并产生增强和激励作用， 通过μ阿片样物质受体活化在自我给药测定中的作用。我们预期的积极影响 这项研究是kratom生物碱对抗神经性疼痛的第一个临床前表征， 和分离，镇痛和强化的潜在机制，将更好地定义 kratom成分的治疗潜力和滥用倾向。

PROJECT SUMMARY Kratom, also known as Mitragyna speciosa, is a controversial plant in the coffee family that contains more than 20 alkaloids, several of which are biologically active, with mitragynine being the most prevalent. Kratom has a fascinating, and mixed, pharmacological profile that combines opioid and stimulant effects, with stimulant effects being most prevalent at low-to-moderate doses and opioid effects presenting with higher doses. Although kratom has been used for centuries in Southeast Asia to counteract fatigue and manage pain, opioid withdrawal, fever and depression, its increased use in the United States has recently been the subject of a FDA public health advisory addressing adverse risks and abuse liability associated with its use. Unfortunately, most information regarding kratom pharmacology has been derived anecdotally from human users. The decisions that scientists, clinicians, and government officials face regarding the potential scheduling of kratom as a controlled substance is limited by a lack of preclinical, experimental data obtained from laboratory animals. While the addictive properties of kratom have garnered the most public attention and are likely due to mu opioid receptor activation, it is the stimulant effects of kratom, likely resulting from enhanced adrenergic transmission, that are especially understudied and perhaps most relevant to its therapeutic potential. Our goal in this R21 application is to provide the first comprehensive study of a kratom alkaloid (mitragynine) in preclinical models of neuropathic pain and self-administration (SA) and to define, and discriminate, the neuroprotective and reinforcing efficacies of mitragynine in terms of receptor mechanisms and sites of action. The overall hypothesis to be tested using rats is that mitragynine reduces chemotherapy-induced neuropathic pain by enhancing adrenergic transmission at α2-adrenoceptors and produces reinforcing and motivational effects in self-administration assays through mu opioid receptor activation. The expected positive impact of our study is the first preclinical characterization of a kratom alkaloid against neuropathic pain and the delineation, and separation, of underlying mechanisms of analgesia and reinforcement that will better define the therapeutic potential and abuse liability of kratom constituents.