Laboratory Model for Heroin Abuse Medications

除了海洛因滥用的持续问题外，处方阿片类药物滥用已经成为一个严重的公共卫生问题。然而，很少有研究系统地研究处方阿片类药物的增强作用，更不知道维持药物，如丁丙诺啡，降低其影响的能力。对实验室动物的研究表明，与芬太尼等高疗效激动剂相比，丁丙诺啡更有效地对抗低或中等疗效的阿片激动剂，如纳布芬或吗啡。使用各种方法，本申请中提出的研究旨在检查疗效不同的阿片激动剂(芬太尼、吗啡)的相对增强、主观、表现和生理效应，并检查两种经常滥用的处方阿片类药物(羟考酮、氢可酮)的效果，其疗效尚未完全确定。研究1将直接比较静脉注射芬太尼、羟考酮、氢可酮、海洛因和吗啡，使用我们在最初资助期间开发的药物与金钱选择程序。研究2将试图通过药物对药物选择程序进一步区分芬太尼、羟考酮和海洛因的效果，以便将剂量的芬太尼和羟考酮作为一系列海洛因的替代品。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)相对于吗啡的作用(研究3-5)。丁丙诺啡通常被认为是u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“假不可逾越”的拮抗剂来表征相对激动剂的疗效。因此，我们将能够在研究3-5中描述相对激动剂的疗效。因此，目前申请中提出的研究将使用各种趋同的方法来确定一系列处方阿片类药物与海洛因相比的相对疗效。最近处方类阿片滥用的增加，丁丙诺啡最近被批准用于治疗阿片依赖，以及关于丁丙诺啡对抗海洛因和氢吗啡以外的阿片类药物作用的信息相对缺乏，使得目前应用中提出的研究具有理论和临床意义。

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.