New Neural Targets for Opioid Use Disorders: Human Studies

描述(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，但滥用和对处方阿片类药物的依赖在过去十年中急剧增加。2006年(SAMHSA，2007b)，估计约有100万人依赖处方阿片类药物(根据DSM-IV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。虽然美国已批准了治疗阿片依赖的现有药物疗法，但最有效的药物(丁丙诺啡和美沙酮)仅限于特定的实践条件，从而限制了患者使用这些药物的可能性。P物质是一种神经激肽，广泛分布于人脑，其受体在涉及情感和奖赏的脑区高表达。最近的证据表明，P物质受体(NK1)的失活，无论是通过基因缺失还是药物阻断，在一系列非人类实验室模型中都显著减弱了阿片类药物的奖赏效应。我们推测，用P物质受体拮抗剂预处理可能会减少MU阿片激动剂的直接药效学作用，这与它们在人类中的滥用倾向和奖赏效应有关。Approant是一种NK1受体拮抗剂，临床上用于止吐。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。将进行两项住院试验，包括双盲、安慰剂对照、随机、受试者内设计，并仔细评估对多维结果的全部剂量-效应和时间作用曲线。实验1将检查急性剂量的阿片类药物滥用者(n=10)的急性剂量羟考酮和急性剂量的口服羟考酮和鼻腔注射羟考酮的效果。药效学结果将包括与滥用潜力、精神运动表现和生理指数有关的受试者和观察者评级的措施。实验2将检查长期给药的效果，并在稳定状态下测试其改变鼻腔内羟考酮的增强效果的能力(n=10)。在这项研究中，将采用累进比率自我给药程序来直接检查阿片类药物的强化。此外，在样本会议期间，将检查在一系列措施上重复使用羟考酮后的药效相互作用。因此，这些研究将为NK1拮抗剂在急性和慢性给药条件下的安全性以及其改变羟考酮滥用易感性和增强特性的潜在疗效提供新的信息。这些研究是对RFA(DA-06-002)的响应，因为它们将提供概念验证数据，并通过评估NK1受体拮抗剂Approant减少阿片类药物在人类中的滥用倾向和增强作用的潜在功效，评估一种新的中枢神经系统靶标--P物质受体的实用性。 与公共健康相关：该项目将测试一种假设，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阿片类药物有关的影响。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目标进行审查。因此，这些在健康人类中进行的研究将提供关于该系统作为开发新的阿片类药物使用障碍治疗药物的目标的潜力的基本信息。

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.