Opioid antagonists such as naloxone can precipitate abstinence signs and symptoms when administered several hours after acute exposure to a short- acting opioid agonist drug. This observation is rather remarkable since abstinence signs are generally associated with chronic exposure to opioid drugs, where they denote the presence of physical dependence. The antagonist precipitated withdrawal signs seen after brief exposure to opioid agonist drug (antagonist sensitivity) may represent the incipient stages of opioid physical dependence. The human pharmacology of opioid antagonist sensitivity is the focus of the present grant project. By examining the pharmacology of antagonist sensitivity, we hope to understand its relationship to development of opioid physical dependence in man. In the present application, our first priority is to complete dose-effect and time course studies to bring this aspect of the project to closure. Our next priority is to establish pharmacological specificity in relation to the physical dependence profile of pretreatment drugs. A third priority, which can be pursued concurrently with other studies, is to explore opiate exposure history of the subject as a potential determinant of individual differences in the antagonist sensitivity response. Specific studies proposed will examine high dose naloxone effects and morphine/naloxone dose interactions in order to clarify interpretation of precipitated abstinence effects (Exp. 1), examine in a single study the full time course of antagonist sensitivity effects from 1 to 36 hours after acute opioid exposure (Exp 2), examine precipitated abstinence intensity as a function of antagonist challenge procedures, particularly the route and speed of antagonist drug administration (Exp 3), examine the intensity and duration of precipitated abstinence effects following pretreatment with several short-acting opioid agonists, mixed agonist-antagonists, and nonopioid drugs (Exps. 6,7), examine the influence of opioid duration of action and receptor occupancy characteristics by comparing precipitated abstinence effects following pretreatment with mu agonists that differ widely on these dimensions including fentanyl, morphine, methadone, buprenorphine (Exps 8 - 10), examine agonist pretreatment and antagonist challenge parameters that influence precipitated abstinence effects in subject lacking opioid exposure histories (Exps. 11 - 14) and finally examine in a prospective study the influence of opioid exposure history (opioid naive versus opioid experienced) on precipitated abstinence responses following brief opioid exposure (Exp 15).Overall, these studies will improve our understanding of acute antagonist sensitivity while clarifying its relationship to the pharmacology/physical dependence profile of opioid and nonopioid drugs and to the development of chronic opioid physical dependence in human.
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