Regulation of gene expression mediated by the opioid receptor and the nociceptin receptor

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In this investigation, we mainly analyzed changes in gene expression induced by opioid analgesics and intravenous anesthetics, using molecular biological, biochemical and electrophysiological methods.Activation of the opioid receptor expressed by transfection of the cloned cDNA in CHO cells induced expression of immediate early genes, c-fos and junB.This induction was inhibited by pertussis toxin and PD98059, suggesting that pertussis toxin-sensitive G-proteins and mitogen- avtivated protein kinase (MAPK) are involved in the signal transduction pathway. This mechanism might be involved in the molecular mechanism of opioid tolerance or dependence, serious side effects of opioid analgesics.Effects of intravenous anesthetics on gene expression in neuronal cells have not been investigated. We found that midazolam induces expression of immediate early gene products, c-Fos and EGR-1, that was blocked by PD98059. Midazolam induced MAPK activation in a time- and dose-dependent manner. The midazolam-induced MAPK activation was blocked by inhibitors of tyrosine kinase and epidermal growth factor receptor. Our results may suggest that intravenous anesthetics induce long-term changes in neural functions by changes in gene expression patterns.Chronic agonist exposure of the NG108-15 cells transformed to express the μ-opioid receptor was demonstrated to cause desensitization of the opioid-induced inhibition of the the N-type Ca^<2+> channel activity. The magnitude of the desensitization was different among various μ-opioid receptor-selective agonists.Effects of volatile anesthetics on Ca^<2+>-activated K^+ channel subtypes were tested by the use of Xenopus oocyte expression system. It was demonstrated that halothane, isoflurane and sevoflurane do not affect the SK subtype, but suppressed the activity of the IK subtype. The physiological implication of this finding remains to be elucidated.