DIFFERENTIAL SENSITIVITIES OF MAMMALIAN NEURONAL AND MUSCLE NICOTINICACETYLCHOLINE-RECEPTORS TO GENERAL-ANESTHETICS

Background: Nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of fast neurotransmitter-gated receptor channels that in cludes the gamma-aminobutyric acid(A) (GABA(A)), glycine and serotonin type 3 (5-HT3) receptors. Most previous work on the interactions of g eneral anesthetics with nAChRs has involved the muscle-type receptor. The authors investigate the effects of general anesthetics on defined mammalian neuronal and muscle nAChRs expressed in Xenopus oocytes. Met hods: Complementary deoxyribonucleic acid (cDNA) or messenger ribonucl eic acid (mRNA) encoding for various neuronal or muscle nAChR subunits was injected into Xenopus oocytes, and the resulting ACh-activated cu rrents were studied using the two-electrode voltage-clamp technique. T he effects of halothane, isoflurane, sevoflurane, and propofol on the peak acetylcholine-induced currents were investigated, and concentrati on-response curves were constructed. Results: The neuronal nAChRs were found to be much more sensitive to general anesthetics than were the muscle nAChRs, with IC50 concentrations being 10- to 35-fold less for the neuronal receptors. For the inhalational general anesthetics, the IC50 concentrations were considerably less than the free aqueous conce ntrations that cause general anesthesia in mammals. In addition, quali tative (dependence on acetylcholine concentration) and quantitative (s teepness of concentration-response curves) differences in the anesthet ic interactions between the neuronal and muscle nAChRs suggest that di fferent mechanisms of inhibition may be involved. Conclusions: Althoug h there is considerable uncertainty about the physiologic roles that n euronal nAChRs play in the central nervous system, their extraordinary sensitivity to general anesthetics, particularly the inhalational age nts, suggests they may mediate some of the effects of general anesthet ics at surgical, or even subanesthetic, concentrations.