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

卡痛生物碱帽柱木碱的治疗秘密：测试临床前神经性疼痛和滥用倾向模型的功效以及潜在阿片类药物和肾上腺素能机制的表征

• 批准号: 9910367
• 负责人: SCOTT M. RAWLS
• 金额: $ 19.81万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-08 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910367
• 关键词: Absence of pain sensation; Acute; Address; Adrenergic Agents; Adrenergic Receptor; Affinity; Agonist; Alkaloids; Analgesics; Anti-Anxiety Agents; Antidepressive Agents; Attention; Behavioral; Biodiversity; Biological; Biological Assay; Cancer Etiology; Cancer Patient; Clinical; Coffee; Data; Dose; Drug usage; Face; Family; Fatigue; Female; Fever; G-Protein-Coupled Receptors; GABA Agonists; Goals; Government Officials; Human; Individual; Inflammation; Injections; Intake; Knowledge; Laboratory Animals; Letters; Link; Literature; Maintenance; Mechanics; Mental Depression; Mitragyna; Modeling; Morphine; Motivation; National Institute of Mental Health; Neuropathy; Opioid; Opioid Antagonist; Opioid Receptor; Opium; Pain; Pain Threshold; Pain management; Papaver; Pharmaceutical Preparations; Pharmacology; Plants; Pre-Clinical Model; Property; Psychological reinforcement; Psychotropic Drugs; Public Health; Rattus; Receptor Activation; Reinforcement Schedule; Reporting; Rewards; Risk; Schedule; Scientist; Self Administration; Site; Source; Southeastern Asia; Spinal; Spinal Cord; Suggestion; Tail; Testing; Therapeutic; United States; analog; base; chemotherapy; conditioned place preference; delta opioid receptor; efficacy testing; experimental study; fascinate; in vitro Assay; male; mu opioid receptors; nanomolar; neuroprotection; opioid use; opioid withdrawal; oxaliplatin; pain model; painful neuropathy; pre-clinical; receptor; screening program; serotonin receptor; transmission process

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.

项目摘要 kratom，也称为Mitragyna Speciosa，是咖啡家族中有争议的植物，其中包含多于 20个生物碱，其中几种具有生物活性，其中Mitragynine是最普遍的。 Kratom有一个 结合阿片类药物和刺激作用的引人入胜且混合的药物剖面和刺激性 在低剂量和较高剂量的阿片类药物作用下，影响最普遍。 尽管Kratom在东南亚已有数百年的历史来抵消疲劳和处理疼痛，但阿片类药物 戒断，发烧和抑郁症，其在美国的使用量增加了 FDA公共卫生咨询涉及与使用相关的广告风险和滥用责任。很遗憾， 有关Kratom药理学的大多数信息都是从人类用户引起的。 科学家，临床医生和政府官员在Kratom的潜在计划方面面临的决定 由于受控物质受到从实验室获得的临床前的实验数据的限制 动物。虽然Kratom的其他属性吸引了最公众的关注，并且很可能是由于 MU阿片受体激活，它是kratom的刺激作用，可能是由于肾上腺增强而引起的 传播，特别是与其治疗潜力最相关的传播。我们的目标 在此R21中，应用于对Kratom生物碱（Mitragynine）的首次全面研究 神经性疼痛和自我给药（SA）的临床前模型，并歧视，歧视 在受体机制和作用部位方面，神经保护性和增强MITRAGYNINE的效率。 使用大鼠进行测试的总体假设是，米特拉吉宁降低了化学疗法诱导的神经性疗法 通过增强α2-肾上腺素受体的肾上腺素传播并产生增强和激励性来疼痛 通过MU阿片受体激活进行自我管理测定的影响。我们的预期积极影响 研究是Kratom生物碱针对神经性疼痛和描述的第一个临床前表征， 和分离，镇痛和加强的潜在机制，可以更好地定义 Kratom的治疗潜力和滥用责任构成。