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，很少有研究系统地检查处方阿片类药物的强化作用，甚至更少了解维持药物，如丁丙诺啡，以减少其作用的能力。实验动物研究表明，与芬太尼等高效阿片激动剂相比，丁丙诺啡在对抗低效或中效阿片激动剂（如纳布啡或吗啡）方面更有效。使用多种方法，当前申请中提出的研究旨在检查不同功效的阿片类激动剂（芬太尼，吗啡）的相对强化，主观，性能和生理效应，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，其功效尚未得到充分表征。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，使用我们在初始资助期间开发的药物与金钱选择程序。研究2将试图进一步区分芬太尼、羟考酮和海洛因使用药物与药物选择程序的影响，这样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将评估丁丙诺啡的拮抗能力

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.