| Our research objective is to elucidate the effects of intravenous and local anesthetics on the biochemical cascade of signal transduction involving receptors of the excitatory amino acids, G protein, calcium influx, nitric oxide synthesis, second messenger system, immediate early oncogene expression, and expression of phosphorylated proteins including p53. We use behavioral and in vivo and in vitro biochemical approaches to correlate molecular events that are influenced by the anesthetics with the associated physiological effects. The dissociative anesthetic, ketamine, is a noncompetitive NMDA antagonist. Our results show k-opioid receptors and G-protein sensitive sites are involved in biochemical and pharmacodynamic responses of ketamine. We established an in vivo model to assess biological functions of nitric oxide. This model involves using parenteral chronic Nw-nitro-L-arginine administration and cGMP assay in the cerebellum. We found that Nw-nitro-L-arginine administration prolongs the hypnotic and hypothermic effects of intravenous anesthetics. Moreover, we showed that the intravenous anesthetic propofol augments AMPA and kainate receptors. Using C-6 glioma and primary glial cells in culture, we showed that the prototype local anesthetic, cocaine, and nitric oxide-generating agents like SNAP and SNP, inhibit glial cell proliferation and DNA, RNA, and protein synthesis. These studies implicate glutamate receptors and nitric oxide-mediated signal transduction in the molecular mechanism of the anesthetics.
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