NK-1 Receptor Antagonism: A Role in Opioid Use Disorders

NK-1 受体拮抗作用：在阿片类药物使用障碍中的作用

• 批准号: 9321363
• 负责人: Sharon L. Walsh
• 金额: $ 57.03万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321363
• 关键词: Acute; Admission activity; Agonist; Anxiety; Attenuated; Behavior; Brain; Buprenorphine; CD94 Antigen; Clinical; Clinical Trials; Cocaine; Crossover Design; Data; Dependence; Dose; Double-Blind Method; Enrollment; Formulation; Genetic; Heroin; Heroin Abuse; Human; Individual; Inpatients; Intravenous; Laboratories; Laboratory Study; Maintenance; Measures; Mediating; Mediation; Methadone; Modeling; Morbidity - disease rate; Naltrexone; Narcotic Antagonists; Nociception; Opiate Addiction; Opioid; Opioid Receptor; Oral; Outcome; Oxycodone; Pain; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Phase; Physical Dependence; Physiological; Placebo Control; Placebos; Procedures; Randomized; Research; Rewards; Role; Safety; Self Administration; Signs and Symptoms; Specific qualifier value; Stress; Substance P; Substance P Receptor; System; Testing; United States; base; behavioral outcome; design; effective therapy; experience; experimental study; healthy volunteer; improved; laboratory experiment; mortality; mu opioid receptors; novel; opioid use; opioid use disorder; opioid withdrawal; overdose death; prescription opioid; response; volunteer

ABSTRACT The United States has experienced a dramatic rise in non-medical use of prescription opioids leading to increased demand for effective treatments for opioid use disorders. Recent evidence suggests that inactivation of Substance P receptors, either through genetic deletion or pharmacological blockade, significantly attenuates the rewarding effects of opioids in an array of laboratory models and suppresses expression of opioid withdrawal signs. Neurokinin 1 (NK1) receptors for Substance P may offer an attractive novel target for a non-addictive treatment approach. This project proposes two inpatient laboratory studies that will enroll individuals with opioid use disorders. These studies will provide the proof-of-concept evidence of NK1 receptor system involvement in mediating the response to opioids as related to abuse potential, reinforcing efficacy and opioid withdrawal in humans. These randomized, placebo-controlled, double-blind, inpatient studies will both employ a within-subject design and enroll otherwise healthy volunteers with current non-medical opioid use with (Exp. 1) and without (Exp. 2) physical dependence on opioids. Both studies will capitalize on the availability of a novel brain-penetrant NK-1 antagonist, VLY-686, for which requisite clinical safety data are available, and the sponsor (Vanda) has agreed to provide support and clinical drug supply. Experiment 1 will examine the effects of maintenance on VLY-686 (100 mg/day) versus placebo on opioid responses with oxycodone on an array of physiological, subjective and behavioral outcomes (self- administration and experimental pain). Experiment 2 will enroll opioid dependent volunteers who will be maintained on oxycodone throughout the study using an established procedure. This study will examine the effects of maintenance on VLY-686 (0 and 100 mg/day) for its ability to attenuate expression of opioid withdrawal signs and symptoms and to attenuate the response to opioid agonist challenge. These studies will provide preliminary safety and key pharmacodynamic data in individuals with opioid use disorders, both with and without physical dependence, and provide proof-of- concept data for the NK-1 receptor system role in mediating critical factors in opioid use disorders.

抽象的 美国的非医学使用阿片类药物的非医学使用急剧上升 对阿片类药物使用障碍有效治疗的需求增加。最近的证据表明 通过遗传缺失或药理学阻断失活P受体， 大大削弱了阿片类药物在一系列实验室模型中的奖励作用，并抑制 阿片类药物戒断迹象的表达。物质P的神经蛋白1（NK1）受体可能会提供吸引人 非添加治疗方法的新目标。该项目提出了两项​​住院实验室研究 将招募患有阿片类药物使用障碍的人。这些研究将提供概念证明证据 NK1受体系统参与介导对阿片类药物的反应与滥用潜力有关的反应， 增强人类的疗效和阿片类药物的戒断。这些随机，安慰剂对照，双盲， 住院研究将采用受试者内部设计，否则将招募其他健康的志愿者 非医学阿片类药物与（exp。1）和没有（exp。2）对阿片类药物的物理依赖性。两项研究都将 利用新型脑p-p-p-1的NK-1拮抗剂VLY-686的可用性，为此必要的临床 可以使用安全数据，并且赞助商（Vanda）已同意提供支持和临床药物供应。 实验1将检查维护对VLY-686（100 mg/day）与安慰剂对阿片类药物的影响 羟考酮对一系列生理，主观和行为结果的反应（自我 给药和实验疼痛）。实验2将注册阿片类药物依赖性志愿者 在整个研究中使用既定的程序保持在羟考酮上。这项研究将检查 维护对VLY-686（0和100 mg/day）的影响，以减轻阿片类药物的表达能力 提取症状和症状，并减轻对阿片类动力学挑战的反应。这些研究会 在患有阿片类药物使用障碍的个体的患者中提供初步安全性和关键的药效学数据，均与 并且没有身体依赖，并为NK-1受体系统在 介导阿片类药物使用障碍中的关键因素。