Chronic treatment with the opioid antagonist drug, naltrexone, increases opioid binding sites in the central nervous system of rats and produces a 50% increase in the antinociceptive (analgesic) action of morphine (supersensitivity). In the mouse, naltrexone treatment produces a 3-fold greater increase in the analgesic potency of morphine than in the rat. While the increase in binding and morphine analgesia is a regularly observed phenomenon, little is known about the pharmacodynamics of opioid antagonist-induced upregulation and supersensitivity. The purpose of this application is to examine the consequences of chronic naltrexone-treatment upon opioid and nonopioid pharmacodynamics and brain opioid binding. We will determine the optimal dose of naltrexone to produce supersensitivity in the rat and mouse, and use this information to examine the development of tolerance and dependence to opioid agonists. The effect of naltrexone treatment on the development of supersensitivity and brain opioid binding in morphine-sensitive and insensitive strains of mice will be determined. In order to examine the role of particular opioid receptors in supersensitivity, the effect of selective opioid agonists will be determined. Since it is not known if supersensitivity is mediated by populations of neurons in the brain or spinal cord, or both, the contribution of these sites will be studied. The potential alterations in psychopharmacologic and toxic response to opioid and nonopioid drugs following opioid antagonist treatment will also be examined as will the possible pharmacokinetic changes in opioid agonists in brain and biofluids following naltrexone treatment. The effects of naltrexone-treatment on stress-induced (cold water swim) analgesia in the rat will be evaluated to assess the contribution of opioid and nonopioid systems in stress. Given that naltrexone has been recently approved for chronic use in the treatment of opioid dependence, these questions are of particular interest, since the possible consequences of upregulation in humans are unknown. Studies outlined in this proposal will systematically examine the functional consequences of opioid antagonist treatment on a variety of opioid and nonopioid effects. These studies will allow us to evaluate the significance, generality and specificity of opioid antagonist-induced upregulation and supersensitivity.
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