New Neural Targets for Opioid Use Disorders: Human Studies

阿片类药物使用障碍的新神经靶点：人类研究

• 批准号: 7914340
• 负责人: Sharon L. Walsh
• 金额: $ 34.26万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914340
• 关键词: Acute; Adult; Affect; Agonist; American; Amygdaloid structure; Antiemetics; Anxiety; Attenuated; Behavior; Brain; Brain region; Buprenorphine; Chronic; Clinical Research; DSM-IV; Data; Dependence; Development; Disease; Dose; Double-Blind Method; Drug Controls; Drug Interactions; Drug usage; Effectiveness; Enrollment; Evaluation; Female; Genetic; Health; Heroin; Hippocampus (Brain); Human; Inpatients; Laboratories; Laboratory Study; Marketing; Measures; Mediation; Methadone; Modeling; Naltrexone; Narcotic Antagonists; Nausea and Vomiting; Neuraxis; Nociception; Nucleus Accumbens; Opiate Addiction; Opioid; Oral; Outcome; Oxycodone; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Physiological; Placebo Control; Policies; Population; Procedures; Property; Psychological reinforcement; Psychomotor Performance; Public Health; Randomized; Recording of previous events; Rewards; Route; Safety; Sampling; Self Administration; Stress; Substance P; Substance P Receptor; Substance-Related Disorders; Surveys; System; Testing; Time; To specify; United States; United States Substance Abuse and Mental Health Services Administration; aprepitant; base; chemotherapy; compliance behavior; design; indexing; male; mu opioid receptors; novel; opioid abuse; prescription opioid; public health relevance; receptor; relating to nervous system; research study; therapy development; volunteer

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.

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，但对处方阿片类药物的滥用和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），国家药物管制政策办公室估计目前有 100 万人对海洛因成瘾。 。虽然美国已有批准用于治疗阿片类药物依赖的药物疗法，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下使用，从而限制了患者的使用。 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大脑区域高度表达。最近的证据表明，通过基因删除或药理学阻断，P 物质受体 (NK1) 失活会显着减弱阿片类药物在一系列非人类实验室模型中的奖励作用。我们假设用 P 物质受体拮抗剂进行预处理可能会减少 mu 阿片类激动剂的直接药效作用，这与其在人类中的滥用倾向和奖励作用有关。阿瑞吡坦是一种 NK1 受体拮抗剂，临床上用于止吐作用。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，并包括对多维结果的完整剂量效应和时间作用曲线进行仔细评估。实验1将检查急性剂量的阿瑞匹坦单独使用以及与急性剂量的口服羟考酮和鼻内羟考酮组合对非依赖性阿片类药物滥用者（n = 10）的影响。药效结果将包括与滥用潜力、精神运动表现和生理指标相关的受试者和观察者评价的测量。实验2将检查阿瑞吡坦长期给药的效果，并测试其在稳态下改变鼻内羟考酮增强作用的能力（n=10）。本研究将采用渐进比例自我给药程序来直接检查阿片类药物的强化。此外，在样品测试期间，将检查在一系列措施中重复给药阿瑞匹坦和羟考酮后的药效学相互作用。因此，这些研究将提供关于 NK1 拮抗剂治疗在急性和慢性给药条件下的安全性及其改变羟考酮滥用倾向和增强特性的潜在功效的新信息。这些研究响应 RFA (DA-06-002)，因为它们将提供概念验证数据，并通过评估 NK1 受体拮抗剂的潜在功效来评估新型 CNS 靶标（P 物质受体）的效用，阿瑞匹坦，以减少阿片类药物对人类的滥用倾向和强化作用。 公共健康相关性：该项目将测试以下假设：阻断人脑中的 P 物质受体可能会减少阿片类药物与其滥用相关的影响。 P 物质系统尚未被视为开发阿片类药物滥用和依赖治疗的潜在目标。因此，这些在健康人类中进行的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目标的潜力的基本信息。