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

摘要 在美国，处方阿片类药物的非医疗使用急剧增加， 对阿片类药物使用障碍的有效治疗的需求增加。最近的证据表明 通过基因缺失或药物阻断使P物质受体失活， 在一系列实验室模型中， 阿片类药物戒断症状的表达。P物质的神经激肽1（NK 1）受体可能提供一种有吸引力的 非成瘾性治疗方法的新靶点。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个体。这些研究将提供概念验证证据， NK 1受体系统参与介导阿片类药物的反应，与滥用潜力有关， 增强人类的疗效和阿片类药物戒断。这些随机、安慰剂对照、双盲、 住院研究将采用受试者内设计，并招募其他健康志愿者， 非医用阿片类药物使用（Exp. 1)没有（Exp。2)对阿片类药物的身体依赖两项研究将 利用一种新的脑渗透性NK-1拮抗剂VLY-686的可用性， 安全性数据可用，申办者（Vanda）已同意提供支持和临床药物供应。 实验1将检查维持VLY-686（100 mg/天）相对于安慰剂对阿片样物质的影响 羟考酮对一系列生理、主观和行为结果的反应（自我， 给药和实验性疼痛）。实验2将招募阿片类药物依赖志愿者， 在整个研究期间使用既定程序维持羟考酮。本研究将探讨 维持对VLY-686（0和100 mg/天）减弱阿片样物质表达的能力的影响 戒断体征和症状，并减弱对阿片样物质激动剂激发的反应。这些研究将 提供阿片类药物使用障碍患者的初步安全性和关键药效学数据， 并且没有身体依赖性，并为NK-1受体系统在 介导阿片类药物使用障碍的关键因素。

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.