Physical dependence is one factor which tends to perpetuate compulsive drug use and addiction and is thus an important component of drug abuse liability. The overall goal of this on-going grant project is to characterize the initiation and early development of opioid physical dependence in humans and to better understand the mechanisms by which physical dependence develops and escalates. This continuation application will build logically on previous studies of acute dependence in order to better understand the role of pharmacological factors including intrinsic drug efficacy in determining the dependence potential of opioid drugs and to begin exploring interventions that might effectively modulate the processes of physical dependence development. The first study will determine whether buprenorphine, a long-acting opioid partial agonist with relatively low efficacy and high receptor affinity, produces less acute physical dependence than does methadone or LAAM. A second study will determine whether, as predicted by certain current theories of tolerance and dependence, naloxone precipitation effects differ for fentanyl, morphine and meperidine as a function of their differing potency/intrinsic efficacy characteristics. Two additional studies will determine whether methadone has higher intrinsic ability to produce acute dependence than does morphine when the drugs are tested at equianalgesic doses and under conditions that remove the influence of receptor occupancy duration. The final three studies proposed examine treatment interventions that might modulate the dependence development process. One study will determine whether treatment with low dose naloxone can interrupt the process of acute dependence development by partially resetting receptors. A second study will determine whether treatment with the opioid peptide dynorphin can reduce the intensity of withdrawal subsequently precipitated by antagonist challenge in an acute dependence model while the final proposed study will determine whether treatment with an NMDA antagonist such as dextromethorphan can modulate acute dependence. Overall, the proposed studies will provide new insights into how various mu active opioids differ in their intrinsic ability to produce physical dependence effects. This information will be useful for understanding the relative advantages and disadvantages of opioid analgesics and of treatment medications with regard to dependence liability. New information will also be obtained about malleability of the dependence development processes by examining pharmacological interventions thought to influence relevant neurochemical mechanisms. Thus, these studies, building logically on previous work of the project, should produce new information with considerable basic scientific value as well as clinical relevance for developing new treatments of opioid drug dependence.
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