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.

项目概要 Kratom，也称为 Mitragyna spiosa，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，其中卡痛叶最常见。 令人着迷的混合药理学特征，结合了阿片类药物和兴奋剂作用，以及兴奋剂 阿片类药物的作用在低至中等剂量时最为普遍，而阿片类药物的作用则在较高剂量时出现。 尽管卡痛叶在东南亚已被用于消除疲劳和控制疼痛已有数百年历史，但阿片类药物 戒断、发烧和抑郁症，其在美国的使用增加最近已成为一个主题 FDA 公共卫生咨询解决了与其使用相关的不良风险和滥用责任。 大多数有关卡痛叶药理学的信息均来自人类使用者。 科学家、附属机构和政府官员面临的有关卡痛叶潜在日程安排的决定 作为受控物质，由于缺乏从实验室获得的临床前实验数据而受到限制 卡痛叶的成瘾特性引起了公众的广泛关注，这可能是由于 mu阿片受体激活，它是卡痛叶的兴奋作用，可能是由于肾上腺素能增强所致 传播，这方面的研究尤其不足，并且可能与其治疗潜力最相关。 在这个 R21 申请中，我们首次对卡痛生物碱（帽柱木碱）进行了全面研究 神经病理性疼痛和自我给药（SA）的临床前模型，并定义和区分 帽柱木碱在受体机制和作用位点方面的神经保护和增强功效。 使用大鼠进行测试的总体假设是帽柱木碱可减少化疗引起的神经病变 通过增强 α2 肾上腺素受体的肾上腺素能传递来减轻疼痛，并产生强化和激励作用 通过 mu 阿片受体激活进行自我给药测定的效果 我们的预期积极影响。 研究是卡痛生物碱对抗神经性疼痛的第一个临床前表征和描述， 和分离镇痛和强化的基本机制，这将更好地定义 卡痛叶成分的治疗潜力和滥用倾向。