Laboratory Model for Heroin Abuse Medications

除了持续存在的海洛因滥用问题外，处方类阿片滥用已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强化作用，甚至更少有人知道维持药物（如丁丙诺啡）减少其作用的能力。在实验室动物中的研究表明，与具有高功效的激动剂（如芬太尼）相比，丁丙诺啡在拮抗具有低或中等功效的阿片激动剂（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被设计为检查在功效方面不同的阿片样物质激动剂（芬太尼、吗啡）的相对强化、主观、性能和生理作用，并检查两种通常滥用的处方阿片样物质（羟考酮、氢可酮）的效果，其功效尚未完全表征。研究1将直接比较静脉芬太尼，羟考酮，氢可酮，海洛因，吗啡使用药物与金钱的选择程序，我们在我们的初始资助期间开发。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性拮抗抗肿瘤活性的能力。 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μ阿片受体的部分激动剂和κ阿片受体的拮抗剂。基于其与阿片受体的缓慢解离，其被用作“假不可逾越的”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中表征相对激动剂疗效。因此，本申请中提出的研究将使用各种趋同方法来表征一系列处方类阿片与海洛因相比的相对疗效。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，以及相对缺乏关于丁丙诺啡拮抗除海洛因和氢吗啡酮以外的阿片类药物作用的能力的信息，使得当前申请中提出的研究在理论上和临床上都具有相关性。

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.