Abstract
BackgroundOur previous studies revealed that application of the inhalation anesthetic, sevoflurane, reversibly repressed the expression of Per2 in the mouse suprachiasmatic nucleus (SCN). We aimed to examine whether sevoflurane directly affects the SCN.MethodsWe performed in vivo and in vitro experiments to investigate rat Per2 expression under sevoflurane-treatment. The in vivo effects of sevoflurane on rPer2 expression were examined by quantitative in situ hybridization with a radioactively-labeled cRNA probe. Additionally, we examined the effect of sevoflurane anesthesia on rest/activity rhythms in the rat. In the in vitro experiments, we applied sevoflurane to SCN explant cultures from Per2-dLuc transgenic rats, and monitored luciferase bioluminescence, representing Per2 promoter activity. Bioluminescence from two peripheral organs, the kidney cortex and the anterior pituitary gland, were also analyzed.ResultsApplication of sevoflurane in rats significantly suppressed Per2 expression in the SCN compared with untreated animals. We observed no sevoflurane-induced phase-shift in the rest/activity rhythms. In the in vitro experiments, the intermittent application of sevoflurane repressed the increase of Per2-dLuc luminescence and led to a phase delay in the Per2-dLuc luminescence rhythm. Sevoflurane treatment did not suppress bioluminescence in the kidney cortex or the anterior pituitary gland.ConclusionThe suppression of Per2-dLuc luminescence by sevoflurane in in vitro SCN cultures isolated from peripheral inputs and other nuclei suggest a direct action of sevoflurane on the SCN itself. That sevoflurane has no such effect on peripheral organs suggests that this action might be mediated through a neuron-specific cellular mechanism or a regulation of the signal transduction between neurons.
Highlights
General anesthesia, which results in unconsciousness and reduced pain perception, has been used clinically for over 150 years, and improvements in its safety have allowed many surgical advances [1,2,3]
Some studies have proposed that ligand-gated ion channels and G protein-coupled receptors are involved in general anesthesia [4,5], but it is unclear whether these proteins alone are responsible for anesthetic effects
We comprehensively investigated the effects of general anesthesia on gene expression by microarray analysis and revealed that sevoflurane, currently the most widely used anesthetic for inhalation anesthesia, affected the expression of 1.5% of 10,000 genes in various rat organs [6]
Summary
General anesthesia, which results in unconsciousness and reduced pain perception, has been used clinically for over 150 years, and improvements in its safety have allowed many surgical advances [1,2,3]. We comprehensively investigated the effects of general anesthesia on gene expression by microarray analysis and revealed that sevoflurane, currently the most widely used anesthetic for inhalation anesthesia, affected the expression of 1.5% of 10,000 genes in various rat organs [6]. Our recent study using quantitative in situ hybridization revealed that mouse Per (mPer2) expression in the SCN was repressed by sevoflurane-treatment [10], and the effect was most prominent when mice were anesthetized in the morning. Only anesthetic treatment in the morning affected the subsequent mPer expression cycle, which showed plasticity in the effect of anesthesia on gene expression [10,11]. Our previous studies revealed that application of the inhalation anesthetic, sevoflurane, reversibly repressed the expression of Per in the mouse suprachiasmatic nucleus (SCN). We aimed to examine whether sevoflurane directly affects the SCN
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