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.
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