Opioid administration, not only results in immediate effects at the neurotransmitter or ion channel levels, but also produces neuronal plasticity mediated by changes in gene expression. The overall objectives of this research are to quantitate and localize the alterations in receptor, neurotransmitter, neuromodulator, and signal transduction gene expression and biosynthesis that occur in opioid tolerant and dependent systems. By use of solution hybridization, ligand binding assays, radioimmunoassays, in situ hybridization and immunocytochemical techniques, the mRNA and/or peptide levels for NMDA, opioid receptors, nitric oxide synthase (NOS), proenkephalin, prodynorphin, c-fos, and tyrosine hydroxylase will be examined in selected CNS areas that are associated with opioid analgesia, tolerance and dependence. The strategy to be employed will use facile solution hybridization, RIA and binding assays to identify CNS areas where opioid induced changes occur. Then a systematic analysis employing additional techniques will be used to localize the changes and to identify additional discriminative markers. These studies will be conducted in animals made tolerant and/or dependent with mu, kappa or delta opioids. The specificity of the opioid induced effects will be enhanced by the use of paradigms in which animals are also co-administered agents (an NMDA antagonist, a NOS inhibitor or an antisense oligonucleotide) that attenuate opioid tolerance and dependence. Excitatory amino acid antagonists (NMDA and non-NMDA), NOS inhibitors, neuronal specific calcium channel blockers and antisense oligos will be evaluated in vivo for their ability to attenuate and/or reverse opioid tolerance. In addition to providing new insights into the biochemical and molecular events that underly opioid tolerance and dependence these studies are designed to discover new, prototypic drug that may be of value as adjuncts in the management of pain and in the treatment of opioid abuse.
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