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

项目总结 KrATOM，也被称为Mitrigyna orosa，是咖啡家族中一种有争议的植物，含有超过 20种生物碱，其中几种具有生物活性，其中最常见的是三尖杉碱。KrATOM有一个 令人着迷的、混合的药理概况，结合了阿片类药物和兴奋剂的作用，以及兴奋剂 低到中等剂量的效果最普遍，高剂量的阿片类药物效果最明显。 尽管KrATOM在东南亚被用来对抗疲劳和止痛已有数百年的历史，但阿片类药物 戒断，发烧和抑郁，它在美国的使用增加最近成为一个主题 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， 大多数关于Krtom药理学的信息都是从人类用户那里传闻而来的。这个 科学家、临床医生和政府官员面临的关于KrATOM潜在时间表的决定 由于受控物质受到缺乏从实验室获得的临床前实验数据的限制 动物。虽然KrATOM的令人上瘾的特性引起了公众的最大关注，可能是因为 MU阿片受体激活，这是KrATOM的刺激作用，可能是由于肾上腺素能增强所致 传播，这一点尤其未被研究，可能与其治疗潜力最相关。我们的目标 在本R21中的应用是提供第一个全面的研究Krtom生物碱(三叶藤碱)在 神经病理性疼痛和自我给药(SA)的临床前模型以及定义和区分 从受体机制和作用部位看米曲林的神经保护和增强作用。 要用大鼠测试的总体假设是，米曲林可以减少化疗引起的神经病变 通过增强α2-肾上腺素受体上的肾上腺素能传递而产生疼痛，并产生强化和激励作用 通过激活u阿片受体在自我给药检测中的作用。我们的预期积极影响 这项研究是Krtom生物碱抗神经病理性疼痛的第一个临床前表征和描绘， 和分离，止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易感性。

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.