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

摘要 美国经历了非医疗使用处方阿片类药物的急剧上升，导致 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显著减弱阿片类药物的奖赏效应并抑制 阿片类药物戒断症状的表达。P物质的神经激肽1(NK1)受体可能提供一种诱人的 非成瘾治疗方法的新靶点。该项目提出了两项住院实验室研究， 将招募有阿片类药物使用障碍的个人。这些研究将提供概念验证证据 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， 增强人类的疗效和阿片类药物的戒断。这些随机的、安慰剂对照的、双盲的 住院研究将采用受试者内设计，并招募其他健康的志愿者，目前 非医用阿片类药物使用(实验1)和无(Exp.2)对阿片类药物的身体依赖。这两项研究都将 利用一种新的脑穿透性NK-1拮抗剂VLY-686的可用性，对其临床应用是必要的 安全数据可用，赞助商(Vanda)已同意提供支持和临床药物供应。 实验1将检验维持剂对VLY-686(100毫克/天)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 给药和实验性疼痛)。实验2将招募阿片依赖志愿者，这些志愿者将 在整个研究过程中使用已建立的程序维持羟考酮。这项研究将考察 维持剂对VLY-686(0和100 mg/d)抑制阿片类药物表达的影响 戒断体征和症状，并减弱对阿片类激动剂挑战的反应。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，并为NK-1受体系统在 阿片类药物使用障碍中的关键因素。

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.