Interactions of intravenous anesthetics with cerebral alpha-2-adrenoceptors

Abstract

Up to date the exact mechanisms of action of anaesthetics on structures of the central nervous system have not been elucidated. Agents acting on central alpha 2-adrenoceptors have been demonstrated to possess potent sedative properties. Beside the classical agonists, general anaesthetics that are currently in clinical use e.g. etomidate have also been shown to act on alpha 2-adrenoceptors. Thus, the aim of this study was to study the effect of the intravenous anaesthetic agents propofol and ketamine on the binding of the specific alpha 2-adrenoceptor agonist paraiodoclonidine at cerebral alpha 2 adrenoceptors. After approval of the local animal care committee brain tissue of six Wistar rats was removed and frozen at -80 degrees C. The tissue was sectioned in 15-20 microns thick slices. After washing in TRIS-buffer (pH = 7.5) the slices were incubated with 2.5 nM 125I-paraiodoclonidine (PIC) for determination of specific binding. Unspecific binding was determined in presence of 200 microM unlabeled clonidine. Displacement experiments were performed in presence of propofol (11-530 microM) and ketamine (52-1100 microM) and evaluated autoradiographically. Average exposure time was three days. All films were then analysed by densitometry. Statistical significance calculated by Student's t-test was assumed at a level of p < 0.05. Only at the highest concentration of propofol and ketamine an effect on PIC binding was noticeable. Neither propofol nor ketamine was able to displace PIC completely from cerebral alpha 2-adrenoceptors. In contrast to other anaesthetics such as etomidate which was demonstrated to displace PIC completely from alpha 2-adrenoceptors, propofol and ketamine exerted only minor effects on the binding of PIC even at concentrations that exceeded clinical concentrations. These data suggest that an additional site of action of these anaesthetics at cerebral alpha 2-adrenoceptors beside the known actions on GABA receptors or NMDA receptors is unlikely.