New Neural Targets for Opioid Use Disorders: Human Studies

描述（由申请人提供）：阿片类药物滥用和依赖是美国日益严重的公共卫生问题。虽然海洛因使用率在过去几年中保持相当稳定，但滥用和依赖处方类阿片的现象在过去十年中急剧增加。2006年（南非毒品和卫生事务部，2007年b），估计约有100万人依赖处方类阿片（根据《精神疾病诊断和统计手册》第四版的标准），而国家药物管制政策办公室估计目前有100万人对海洛因上瘾。虽然现有药物疗法已在美国获批用于治疗阿片类药物依赖，但最有效的药物（丁丙诺啡和美沙酮）仅限于在特定的实践条件下使用，因此限制了患者的可用性。P物质是一种神经激肽，广泛分布于人脑中，其受体在与情感和奖赏有关的脑区高度表达。最近的证据表明，P物质受体（NK 1）的失活，无论是通过基因缺失或药理学阻断，显着减弱阿片类药物在一系列非人类实验室模型的奖励作用。我们假设，用P物质受体拮抗剂预处理可能会减少μ阿片受体激动剂的直接药效学作用，这些作用与其在人类中的滥用倾向和奖励效应有关。阿瑞匹坦是一种NK 1受体拮抗剂，临床上用于其止吐作用。拟议的研究将招募有非法阿片类药物使用史的健康成年男性和女性志愿者。将进行两项住院实验，其中包括双盲、安慰剂对照、随机、受试者内设计，并包括对多维结局的完整剂量效应和时间作用曲线的仔细评价。实验1将在非依赖性阿片类药物滥用者（n=10）中检查急性剂量的阿瑞匹坦单独给药以及与急性剂量的口服羟考酮和鼻内羟考酮联合给药的作用。药效学结局将包括与滥用可能性、心理表现和生理指标相关的受试者和非受试者评定指标。实验2将检查阿瑞吡坦长期给药的作用，并测试其在稳态下改变鼻内羟考酮的增强作用的能力（n=10）。本研究将采用渐进比例自我给药程序直接检查阿片类药物强化。此外，将在采样期间检查阿瑞匹坦与羟考酮重复给药后的药效学相互作用（一系列指标）。因此，这些研究将提供关于急性和慢性给药条件下NK 1拮抗剂治疗的安全性及其改变羟考酮滥用倾向和强化性质的潜在疗效的新信息。这些研究响应RFA（DA-06-002），因为它们将提供概念验证数据，并通过评价NK 1受体拮抗剂阿瑞匹坦降低阿片类药物在人体中滥用倾向和强化作用的潜在疗效，评估新型CNS靶点P物质受体的效用。 公共卫生相关性：该项目将检验这样一种假设，即阻断人脑中的P物质受体可能会减少阿片类药物与滥用有关的影响。尚未将P物质系统作为开发阿片类药物滥用和依赖治疗的潜在靶点进行研究。因此，在健康人群中进行的这些研究将提供有关该系统作为阿片类药物使用障碍新治疗药物开发靶点的潜力的基本信息。

DESCRIPTION (provided by applicant): Opioid abuse and dependence are growing public health problems in the United States. While rates of heroin use have remained fairly stable over the past several years, abuse and dependence on prescription opioids have shown sharp increases over the past decade. In 2006 (SAMHSA, 2007b), it was estimated that approximately one million people were prescription opioid-dependent (based upon DSM-IV criteria) adding to the current one million people estimated by the Office of National Drug Control Policy to be addicted to heroin. While there are existing pharmacotherapies approved for the treatment of opioid dependence in the United States, the most efficacious (buprenorphine and methadone) are restricted in use to specified practice conditions, thus limiting their availability to patients. Substance P, a neurokinin peptide, is widely distributed throughout human brain and its receptors are highly expressed in brain regions involved in affect and reward. Recent evidence suggests that inactivation of substance P receptors (NK1), either through genetic deletion or pharmacological blockade, significantly attenuates the rewarding effects of opioids in an array of non-human laboratory models. We hypothesize that pretreatment with a substance P receptor antagonist may reduce the direct pharmacodynamic actions of mu opioid agonists related to their abuse liability and rewarding effects in humans. Aprepitant is a NK1 receptor antagonist used clinically for its anti-emetic action. The proposed studies will enroll healthy adult male and female volunteers with histories of illicit opioid use. Two inpatient experiments will be conducted that incorporate double-blind, placebo-controlled, randomized, within-subject designs, and include careful evaluation of full dose-effect and time action curves on multi-dimensional outcomes. Experiment 1 will examine the effects of acute doses of aprepitant alone and in combination with acute doses of oral oxycodone and intranasal oxycodone in non-dependent opioid abusers (n=10). Pharmacodynamic outcomes will include subject- and observer-rated measures related to abuse potential, psychomotor performance and physiological indices. Experiment 2 will examine the effects of chronic dosing with aprepitant and test its ability at steady state to alter the reinforcing effects of intranasal oxycodone (n=10). A progressive ratio self-administration procedure will be employed in this study to examine directly opioid reinforcement. Additionally, the pharmacodynamic interactions after repeated dosing of aprepitant with oxycodone on an array of measures will be examined during the sample sessions. Thus, these studies will provide new information on the safety of NK1 antagonist treatment under both acute and chronic dosing conditions and on its potential efficacy to alter the abuse liability and reinforcing properties of oxycodone. These studies are responsive to the RFA (DA-06-002) as they will provide proof-of-concept data and assess the utility of a novel CNS target, the substance P receptor, by evaluating the potential efficacy of an NK1 receptor antagonist, aprepitant, to reduce the abuse liability and reinforcing effects of opioids in humans. PUBLIC HEALTH RELEVANCE: This project will test the hypothesis that blockade of substance P receptors in human brain may reduce the effects of opioids related to their abuse. The substance P system has not been examined as a potential target for the development of treatments for opioid abuse and dependence. Thus, these studies, conducted in healthy humans, will provide fundamental information regarding the potential for this system as a target for development of new treatment agents for opioid use disorders.