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Laboratory Model for Heroin Abuse Medications

海洛因滥用药物的实验室模型

基本信息

批准号：
7628363
负责人：
SANDRA D COMER
金额：
$ 54.56万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7628363
关键词：
Absence of pain sensation Adverse effects Agonist Alprazolam Analgesics Benign Benzodiazepines Biological Assay Buprenorphine Case Study Cessation of life Clinical Condition Dissociation Dose Drug usage Fentanyl Funding Heroin Heroin Abuse Human Hydrocodone Hydromorphone Individual Intravenous Laboratories Laboratory Animals Maintenance Measures Methods Midazolam Modeling Morphine Nalbuphine Naloxone Numbers Opiate Addiction Opioid Opioid Receptor Overdose Oxycodone Participant Performance Pharmaceutical Preparations Physiological Procedures Public Health Range Rate Rattus Relative (related person)Reporting Research Research Personnel Respiration Saline Self Administration Sum Testing United States United States Food and Drug Administration Withdrawal base clinically relevant day design drug efficacy fentanyl abuse kappa opioid receptors mu opioid receptors opioid abuse preclinical study prescription document prescription procedure reinforcer respiratory response

项目摘要

In addition to the ongoing problem of heroin abuse, prescription opioid abuse has been emerging as a serious public health concern. However, few studies have systematically examined the reinforcing effects of prescription opioids, and even less is known about the ability of maintenance medications, such as buprenorphine, to reduce their effects. Studies in laboratory animals have shown that buprenorphine is more effective in antagonizing opioid agonists with low or intermediate efficacy, such as nalbuphine or morphine, compared to agonists with high efficacy, such as fentanyl. Using a variety of methods, the studies proposed in the current application are designed to examine the relative reinforcing, subjective, performance, and physiological effects of opioid agonists that vary in efficacy (fentanyl, morphine) and to examine the effects of two commonly abused prescription opioids (oxycodone, hydrocodone) whose efficacies have not been fully characterized. Study 1 will directly compare intravenous fentanyl, oxycodone, hydrocodone, heroin, and morphine using the drug versus money choice procedure that we developed during our initial funding period. Study 2 will attempt to further differentiate the effects of fentanyl, oxycodone and heroin using a drug versus drug choice procedure such that doses of fentanyl and oxycodone will be available as alternatives to a range of doses of heroin. Studies 3-5 will evaluate the ability of buprenorphine to differentially antagonize the effects of fentanyl (Study 3), oxycodone (Study 4), and hydrocodone (Study 5), relative to morphine (Studies 3-5).Buprenorphine is typically considered to be a partial agonist at mu opioid receptors and an antagonist at kappa opioid receptors. Based on its slow dissociation from opioid receptors, it been used as a "pseudo-insurmountable" antagonist to characterize relative agonist efficacy. Thus we will be able to characterize relative agonist efficacy in Studies 3-5. The studies proposed in the current application will therefore use a variety of convergent approaches to characterize the relative efficacy of a range of prescription opioids compared to heroin. The recent increases in prescription opioid abuse, the recent approval of buprenorphine for treating opioid dependence, and the relative lack of information about buprenorphine's ability to antagonize the effects of opioids other than heroin and hydromorphone make the studies proposed in the current application both theoretically and clinically relevant.

除了持续存在的海洛因滥用问题外，处方阿片类药物滥用也已成为一个严重的公共卫生问题。然而，很少有研究系统地检验处方阿片类药物的增强作用，而且对于丁丙诺啡等维持药物减轻其作用的能力知之甚少。对实验动物的研究表明，与高效能激动剂（如芬太尼）相比，丁丙诺啡在拮抗低效或中效阿片类激动剂（如纳布啡或吗啡）方面更有效。使用多种方法，本申请中提出的研究旨在检查功效不同的阿片类激动剂（芬太尼、吗啡）的相对强化、主观、性能和生理作用，并检查两种常见滥用的处方阿片类药物（羟考酮、氢可酮）的作用，其功效尚未完全表征。研究 1 将使用我们在最初资助期间开发的药物与金钱选择程序直接比较静脉注射芬太尼、羟考酮、氢可酮、海洛因和吗啡。研究2将尝试使用药物与药物选择程序进一步区分芬太尼、羟考酮和海洛因的作用，以便芬太尼和羟考酮的剂量将可作为一系列剂量的海洛因的替代品。研究 3-5 将评估丁丙诺啡差异拮抗芬太尼（研究 3）、羟考酮（研究 4）和氢可酮（研究 5）相对于吗啡（研究 3-5）的作用。丁丙诺啡通常被认为是 mu 阿片受体的部分激动剂和 kappa 阿片受体的拮抗剂。基于其与阿片受体的缓慢解离，它被用作“伪不可克服”拮抗剂来表征相对激动剂功效。因此，我们将能够在研究 3-5 中描述相对激动剂功效。因此，本申请中提出的研究将使用各种聚合方法来表征一系列处方阿片类药物与海洛因相比的相对功效。最近处方阿片类药物滥用的增加、最近批准丁丙诺啡用于治疗阿片类药物依赖、以及关于丁丙诺啡拮抗海洛因和氢吗啡酮以外的阿片类药物作用的能力的信息相对缺乏，使得本申请中提出的研究在理论上和临床上都具有相关性。