We will continue clinical analgesic assays and pharmacokinetic studies to determine whether 1, Alpha-acetylmethadol (LAAM), a drug biotransformed to active metabolites, has any advantages over conventional narcotics in the management of pain due to cancer. We will develop a pharmacokinetic model for LAAM in maintenance patients to assist in the individualization of dosing during induction and complete pharmacologic and pharmacokinetic studies in the rat. This proposal has two new main objectives. The first is to develop a novel method for the simultaneous quantitation of the precursors and products of endorphin, enkephalin and dynorphin biosynthesis. This method will be applied to studies of the effects of opioid agonist and antagonist drugs on opioid peptide biosynthesis in the selected CNS tissues (striatum, hippocampus, hypothalamus, anterior and intermediate-posterior lobe) of rats and guinea pigs. The dosing schedules to be used are based on our pharmacokinetic studies and will allow sustained plasma drug levels during treatment and produce tolerance and physical dependence. These studies will provide the first comprehensive assessment of the effects of chronic treatment with opiate agonist and antagonist drugs on the biosynthesis of each of the three opioid peptide families. The time-course of appearance and disappearance of changes in CNS opioid peptides in tolerant/dependent animals should have important implications for drug abuse and pain research. The second main objective is to examine the biosynthesis and release of adrenal enkephalin peptides and the levels of proenkephalin-mRNA in four species exposed to opiates or stressors. In these studies we will examine the influence of these treatments on enkephalin peptides and mRNA in unilaterally denervated animals. In this way we can define the role of neuroregulation on enkephalin biosynthesis and identify the site(s) where opiates and/or stressors may act to modify adrenal enkephalin peptide biosynthesis and release. These studies may provide important new information on the role of adrenal enkephalins in stress-analgesia. This researach will require high performance liquid chromatographic and radioimmunoassay methods.
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