The objective of this project is to address the relationship between opioid binding sites and pharmacodynamic potency of opioid agonists. Opioid receptor density and opioid agonist potency can be reliably altered by opioid antagonists, opioid agonists and CNS stimulants (e.g., cocaine and amphetamine). It is important to examine the pharmacologic and biochemical consequences of these drug treatments since they include drugs of abuse and significant tools in the clinical management of pain and drug abuse. The proposed studies will explore the factors that mediate increases (upregulation) in opioid binding sites in the CNS. The effect of CNS stimulants and endocrine factors on opioid antagonist-induced upregulation will be studies. CNS stimulants and opioid agonists can also produce receptor upregulation. Studies will investigate the common mechanism that converge on opioid receptor upregulation. Parallel pharmacodynamic studies using receptor selective agonists, and standard opioid analgesics, will assess the functional consequences of receptor upregulation. Parallel pharmacodynamic studies using receptor selective agonists, and standard opioid analgesics, will assess the functional consequences of receptor changes. The relationship between receptors and pharmacodynamic response will also be examined in different species. These studies will build on the differences between the rat and mouse in terms of opioid potency and receptor characteristics. The differences in CNS stimulant potentiation of opioid agonist potency at mu and omega spinal cord and brain opioid receptors will be examined. We will assess in a simple in vitro system the mechanism by which CNS stimulants reliably increase opioid receptor density. The in vivo effects of CNS stimulants on opioid binding in the CNS will also be evaluated. We will examine alterations in opioid receptor-effector coupling using pertussis toxin, a bacterial toxin which interferes with opioid mediated effects. Using binding and pharmacodynamic assays, we will explore the effects of the toxin on opioid actions including analgesia, tolerance and toxicity mediated by specific opioid receptors. The overall goal is to probe the nature of opioid pharmacodynamics and receptor regulation. These studies will provide an opportunity to develop a more complete understanding of how opioid effects (analgesia, tolerance, dependence, toxicity), as well as the actions of cocaine and amphetamine, might be mediated. The proposed studies may increase understanding of the basic mechanisms of drug abuse and pain and may provide important practical information for developing new strategies for treatment.
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