Sodium channels and the synaptic mechanisms of inhaled anaesthetics
2009; Elsevier BV; Volume: 103; Issue: 1 Linguagem: Inglês
10.1093/bja/aep144
ISSN1471-6771
Autores Tópico(s)Nicotinic Acetylcholine Receptors Study
ResumoGeneral anaesthetics act in an agent-specific manner on synaptic transmission in the central nervous system by enhancing inhibitory transmission and reducing excitatory transmission. The synaptic mechanisms of general anaesthetics involve both presynaptic effects on transmitter release and postsynaptic effects on receptor function. The halogenated volatile anaesthetics inhibit neuronal voltage-gated Na+ channels at clinical concentrations. Reductions in neurotransmitter release by volatile anaesthetics involve inhibition of presynaptic action potentials as a result of Na+ channel blockade. Although voltage-gated ion channels have been assumed to be insensitive to general anaesthetics, it is now evident that clinical concentrations of volatile anaesthetics inhibit Na+ channels in isolated rat nerve terminals and neurons, as well as heterologously expressed mammalian Na+ channel α subunits. Voltage-gated Na+ channels have emerged as promising targets for some of the effects of the inhaled anaesthetics. Knowledge of the synaptic mechanisms of general anaesthetics is essential for optimization of anaesthetic techniques for advanced surgical procedures and for the development of improved anaesthetics. General anaesthetics act in an agent-specific manner on synaptic transmission in the central nervous system by enhancing inhibitory transmission and reducing excitatory transmission. The synaptic mechanisms of general anaesthetics involve both presynaptic effects on transmitter release and postsynaptic effects on receptor function. The halogenated volatile anaesthetics inhibit neuronal voltage-gated Na+ channels at clinical concentrations. Reductions in neurotransmitter release by volatile anaesthetics involve inhibition of presynaptic action potentials as a result of Na+ channel blockade. Although voltage-gated ion channels have been assumed to be insensitive to general anaesthetics, it is now evident that clinical concentrations of volatile anaesthetics inhibit Na+ channels in isolated rat nerve terminals and neurons, as well as heterologously expressed mammalian Na+ channel α subunits. Voltage-gated Na+ channels have emerged as promising targets for some of the effects of the inhaled anaesthetics. Knowledge of the synaptic mechanisms of general anaesthetics is essential for optimization of anaesthetic techniques for advanced surgical procedures and for the development of improved anaesthetics. The pharmacology and toxicology of general anaesthetics are remarkably incomplete for such a widely used and clinically important class of drugs. Despite their widespread clinical use, our understanding of the molecular and cellular mechanisms of general anaesthetic action in the CNS is insufficient to explain how any anaesthetic produces amnesia, unconsciousness, or immobilization (at increasing doses), the cardinal clinical features of general anaesthesia. Early optimism that potentiation of ligand-gated ion channel receptors for inhibitory neurotransmitters like γ-aminobutyric (GABA) acid and/or glycine might underlie the actions of all anaesthetics has given way to current concepts of multiple agent-specific mechanisms underlying the diverse features of anaesthesia.27Hemmings Jr, HC Akabas MH Goldstein PA Trudell JR Orser BA Harrison NL Emerging molecular mechanisms of general anesthetic action.Trends Pharmacol Sci. 2005; 26: 503-510Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar 81Sonner JM Antognini JF Dutton RC et al.Inhaled anesthetics and immobility: mechanisms, mysteries, and minimum alveolar anesthetic concentration.Anesth Analg. 2003; 97: 718-740Crossref PubMed Scopus (271) Google Scholar It is now clear the general anaesthetics act at multiple anatomic sites in the nervous system to produce these distinct behavioural effects involving actions on multiple molecular targets.64Pittson S Himmel AM MacIver MB Multiple synaptic and membrane sites of anesthetic action in the CA1 region of rat hippocampal slices.BMC Neurosci. 2004; 5: 52Crossref PubMed Scopus (53) Google Scholar 75Rudolph U Antkowiak B Molecular and neuronal substrates for general anaesthetics.Nat Rev Neurosci. 2004; 5: 709-720Crossref PubMed Scopus (590) Google Scholar For example, there is now convincing evidence that volatile anaesthetics produce immobilization by effects in the spinal cord, while amnesia and unconsiousness involve distinct supraspinal mechanisms.1Antognini JF Schwartz K Exaggerated anesthetic requirements in the preferentially anesthetized brain.Anesthesiology. 1993; 79: 1244-1249Crossref PubMed Scopus (450) Google Scholar 15Eger II, EI Raines DE Shafer SL Hemmings Jr, HC Sonner JM Is a new paradigm needed to explain how inhaled anesthetics produce immobility?.Anesth Analg. 2008; 107: 832-848Crossref PubMed Scopus (74) Google Scholar 66Rampil IJ Mason P Singh H Anesthetic potency (MAC) is independent of forebrain structures in the rat.Anesthesiology. 1993; 78: 707-712Crossref PubMed Scopus (441) Google Scholar Ion channels have emerged as the most likely molecular targets for general anaesthetics. Neurotransmitter-gated ion channels, in particular GABAA, glycine, and N-methyl-d-aspartate (NMDA)-type glutamate receptors, are leading candidates due to their appropriate central nervous system (CNS) distributions, essential physiological roles in inhibitory and excitatory synaptic transmission, and sensitivities of one or more of these channels to clinically relevant concentrations of all anaesthetics.15Eger II, EI Raines DE Shafer SL Hemmings Jr, HC Sonner JM Is a new paradigm needed to explain how inhaled anesthetics produce immobility?.Anesth Analg. 2008; 107: 832-848Crossref PubMed Scopus (74) Google Scholar 27Hemmings Jr, HC Akabas MH Goldstein PA Trudell JR Orser BA Harrison NL Emerging molecular mechanisms of general anesthetic action.Trends Pharmacol Sci. 2005; 26: 503-510Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar 102Yamakura T Bertaccini E Trudell JR Harris RA Anesthetics and ion channels: molecular models and sites of action.Annu Rev Pharmacol Toxicol. 2001; 41: 23-51Crossref PubMed Scopus (232) Google Scholar 103Yamakura T Harris RA Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol.Anesthesiology. 2000; 93: 1095-1101Crossref PubMed Scopus (291) Google Scholar Broadly speaking, general anaesthetic targets vary between the major classes of anaesthetics. Two classes of inhaled anaesthetics can be distinguished based on their distinct pharmacological. properties: (i) the potent inhaled (volatile) anaesthetics exhibit positive modulation of GABAA receptors, and also produce significant anaesthesia-compatible effects on a number of other receptors/channels including enhancement of inhibitory glycine receptors, inhibition of excitatory NMDA-type glutamate and neuronal nicotinic acetylcholine receptors, activation of two-pore domain K2P channels and leak K+ channels,59Patel AJ Honore E Anesthetic-sensitive 2P domain K+ channels.Anesthesiology. 2001; 95: 1013-1021Crossref PubMed Scopus (88) Google Scholar 79Sirois JE Lynch III, C Bayliss DA Convergent and reciprocal modulation of a leak K+ current and I(h) by an inhalational anaesthetic and neurotransmitters in rat brainstem motoneurones.J Physiol. 2002; 541: 717-729Crossref PubMed Scopus (75) Google Scholar and inhibition of presynaptic Na+ channels (see in what follows); and (ii) the gaseous inhaled anaesthetics, which include cyclopropane, nitrous oxide, and xenon, are inactive at GABAA receptors, but block NMDA receptors and activate certain K2P channels at clinical concentrations.23Gruss M Bushell TJ Bright DP et al.Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane.Mol Pharmacol. 2004; 65: 443-452Crossref PubMed Scopus (251) Google Scholar Intravenous anaesthetics like propofol and etomidate represent more potent and specific positive modulators of GABAA receptors, and the i.v. anaesthetic ketamine is a more potent and specific blocker of NMDA receptors.103Yamakura T Harris RA Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol.Anesthesiology. 2000; 93: 1095-1101Crossref PubMed Scopus (291) Google Scholar Here I review accumulating evidence that suggests that some of the effects of volatile anaesthetics are mediated by inhibition of neuronal voltage-gated Na+ channels, an ion channel family often overlooked as a putative target for general anaesthesia (though widely recognized as the principal target for local anaesthetics). General anaesthetics depress fast excitatory and enhance fast inhibitory synaptic transmission mediated primarily by glutamate and GABA (γ-aminobutyric acid), respectively.27Hemmings Jr, HC Akabas MH Goldstein PA Trudell JR Orser BA Harrison NL Emerging molecular mechanisms of general anesthetic action.Trends Pharmacol Sci. 2005; 26: 503-510Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar 62Perouansky M Hemmings HC Jr Presynaptic actions of general anesthetics.in: Antognini JF Carlens E Raines D Neural Mechanisms of Anesthesia. Humana Press, Totowa, NJ2003: 345-370Google Scholar 81Sonner JM Antognini JF Dutton RC et al.Inhaled anesthetics and immobility: mechanisms, mysteries, and minimum alveolar anesthetic concentration.Anesth Analg. 2003; 97: 718-740Crossref PubMed Scopus (271) Google Scholar The relative importance of anaesthetic effects on excitatory vs inhibitory synaptic transmission and the mechanisms involved are less clear. Prolongation of synaptic inhibition by modulation of postsynaptic GABAA receptor function at GABAergic synapses is recognized as an important component of the depressant effects of volatile anaesthetics and of several i.v. anaesthetics at clinical concentrations,21Gage PW Robertson B Prolongation of inhibitory postsynaptic currents by pentobarbitone, halothane and ketamine in CA1 pyramidal cells in rat hippocampus.Br J Pharmacol. 1985; 85: 675-681Crossref PubMed Scopus (148) Google Scholar 30Jones MV Harrison NL Effects of volatile anesthetics on the kinetics of inhibitory postsynaptic currents in cultured rat hippocampal neurons.J Neurophysiol. 1993; 70: 1339-1349Crossref PubMed Scopus (154) Google Scholar 49Nicoll RA Eccles JC Oshima T Rubia F Prolongation of hippocampal inhibitory postsynaptic potentials by barbiturates.Nature. 1975; 258: 625-626Crossref PubMed Scopus (259) Google Scholar 108Zimmerman SA Jones MV Harrison NL Potentiation of gamma-aminobutyric acid A receptor Cl-current correlates with in vivo anesthetic potency.J Pharmacol Exp Ther. 1994; 270: 987-991PubMed Google Scholar and significant progress has been made in identifying critical anaesthetic binding sites on GABAA receptors.27Hemmings Jr, HC Akabas MH Goldstein PA Trudell JR Orser BA Harrison NL Emerging molecular mechanisms of general anesthetic action.Trends Pharmacol Sci. 2005; 26: 503-510Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar More recent studies have implicated anaesthetic actions on tonic inhibitory currents mediated by extrasynaptic GABAA receptors as well as enhanced release of GABA mediated by a presynaptic increase in miniature inhibitory postsynaptic current (mIPSC) frequency (see in what follows). Evidence also supports depression of excitatory transmission at clinical concentrations of many general anaesthetics.40MacIver MB Mikulec AA Amagasu SM Monroe FA Volatile anesthetics depress glutamate transmission via presynaptic actions.Anesthesiology. 1996; 85: 823-834Crossref PubMed Scopus (182) Google Scholar 53Ouanonou A Zhang Y Zhang L Changes in the calcium dependence of glutamate transmission in the hippocampal CA1 region after brief hypoxia-hypoglycemia.J Neurophysiol. 1999; 82: 1147-1155PubMed Google Scholar 61Perouansky M Baranov D Salamn M Yaari Y Effects of halothane on glutamate receptor-mediated excitatory postsynaptic currents: A patch-clamp study in adult mouse hippocampal slices.Anesthesiology. 1995; 83: 109-119Crossref PubMed Scopus (105) Google Scholar 91Wakasugi M Hirota K Roth S Ito Y The effects of general anesthetics agents on excitatory and inhibitor synaptic transmission in area CA1 of the rat hippocampus in vitro.Anesth Analg. 1999; 88: 676-680Crossref PubMed Scopus (106) Google Scholar The molecular mechanisms of these depressant effects on excitatory transmission are less clear, but could include depressed membrane excitability,64Pittson S Himmel AM MacIver MB Multiple synaptic and membrane sites of anesthetic action in the CA1 region of rat hippocampal slices.BMC Neurosci. 2004; 5: 52Crossref PubMed Scopus (53) Google Scholar depressed presynaptic action potential conduction,4Berg-Johnsen J Langmoen IA The effect of isoflurane on unmyelinated and myelinated fibres in the rat brain.Acta Physiology Scand. 1986; 127: 87-93Crossref PubMed Scopus (40) Google Scholar 44Mikulec AA Pittson S Amagasu SM Monroe FA Maclver MB Halothane depresses action potential conduction in hippocampal axons.Brain Res. 1998; 796: 231-238Crossref PubMed Scopus (35) Google Scholar 54OuYang W Hemmings Jr, HC Depression by isoflurane of the action potential and underlying voltage-gated ion currents in isolated rat neurohypophysial nerve terminals.J Pharmacol Exp Ther. 2005; 312: 801-808Crossref PubMed Scopus (39) Google Scholar 100Wu XS Sun JY Evers AS Crowder M Wu LG Isoflurane inhibits transmitter release and the presynaptic action potential.Anesthesiology. 2004; 100: 663-670Crossref PubMed Scopus (114) Google Scholar inhibition of transmitter release,43Miao N Frazer MJ Lynch III, C Volatile anesthetics depress Ca2+ transients and glutamate release in isolated cerebral synaptosomes.Anesthesiology. 1995; 83: 593-603Crossref PubMed Scopus (96) Google Scholar 77Schlame M Hemmings Jr, HC Inhibition by volatile anesthetics of endogenous glutamate release from synaptosomes by a presynaptic mechanism.Anesthesiology. 1995; 82: 1406-1416Crossref PubMed Scopus (121) Google Scholar and/or blockade of postsynaptic receptors. The latter is the principal mechanism for ketamine7Brockmeyer DM Kendig JJ Selective effects of ketamine on amino acid-mediated pathways in neonatal rat spinal cord.Br J Anaesth. 1995; 74: 79-84Crossref PubMed Scopus (71) Google Scholar and for the gaseous anaesthetics xenon,103Yamakura T Harris RA Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol.Anesthesiology. 2000; 93: 1095-1101Crossref PubMed Scopus (291) Google Scholar nitrous oxide,42Mennerick S Jevtovic-Todorovic V Todorovic SM Shen W Olney JW Zorumski CF Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures.J Neurosci. 1998; 18: 9716-9726Crossref PubMed Google Scholar and cyclopropane.80Solt K Eger II, EI Raines DE Differential modulation of human N-methyl-D-aspartate receptors by structurally diverse general anesthetics.Anesth Analg. 2006; 102: 1407-1411Crossref PubMed Scopus (80) Google Scholar Blockade of postsynaptic glutamate receptors has been shown to contribute to the effects of volatile anaesthetics at some synapses.12Dickinson R Peterson BK Banks P et al.Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor by the anesthetics xenon and isoflurane: evidence from molecular modeling and electrophysiology.Anesthesiology. 2007; 107: 756-767Crossref PubMed Scopus (187) Google Scholar 25Haseneder R Kratzer S Kochs E et al.Xenon reduces N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated synaptic transmission in the amygdala.Anesthesiology. 2008; 109: 998-1006Crossref PubMed Scopus (35) Google Scholar The roles of enhanced inhibitory transmission vs reduced excitatory transmission to the overall depression of neuronal activity in anaesthesia likely vary between specific networks.64Pittson S Himmel AM MacIver MB Multiple synaptic and membrane sites of anesthetic action in the CA1 region of rat hippocampal slices.BMC Neurosci. 2004; 5: 52Crossref PubMed Scopus (53) Google Scholar 85Stuth EA Krolo M Tonkovic-Capin M Hopp FA Kampine JP Zuperku EJ Effects of halothane on synaptic neurotransmission to medullary expiratory neurons in the ventral respiratory group of dogs.Anesthesiology. 1999; 91: 804-814Crossref PubMed Scopus (18) Google Scholar The relative contributions of presynaptic vs postsynaptic anaesthetic effects on synaptic transmission have been difficult to resolve.11de Sousa SL Dickinson R Lieb WR Franks NP Contrasting synaptic actions of the inhalational general anesthetics isoflurane and xenon.Anesthesiology. 2000; 92: 1055-1066Crossref PubMed Scopus (214) Google Scholar 19Franks NP Lieb WR Molecular and cellular mechanisms of general anaesthesia.Nature. 1994; 367: 607-613Crossref PubMed Scopus (1613) Google Scholar Electrophysiological evidence supports both presynaptic (release) and postsynaptic (receptor) mechanisms for the synaptic actions of general anaesthetics. Intravenous anaesthetics and volatile anaesthetics decrease excitatory postsynaptic potentials (EPSPs) in spinal33Kullman DM Martin RL Redman SJ Reduction by general anesthetics of group Ia excitatory postsynaptic potentials and currents in the cat spinal cord.J Physiol (London). 1989; 412: 277-296Crossref Scopus (43) Google Scholar 93Weakly JN Effect of barbiturate on quantal synaptic transmission in spinal motoneurones.J Physiol (London). 1969; 204: 63-77Crossref Scopus (164) Google Scholar and hippocampal neurons,5Berg-Johnsen J Langmoen IA The effects of isoflurane on excitatory synaptic transmission in the rat hippocampus.Acta Anaesthesiol Scand. 1992; 36: 350-354Crossref PubMed Scopus (55) Google Scholar 40MacIver MB Mikulec AA Amagasu SM Monroe FA Volatile anesthetics depress glutamate transmission via presynaptic actions.Anesthesiology. 1996; 85: 823-834Crossref PubMed Scopus (182) Google Scholar 61Perouansky M Baranov D Salamn M Yaari Y Effects of halothane on glutamate receptor-mediated excitatory postsynaptic currents: A patch-clamp study in adult mouse hippocampal slices.Anesthesiology. 1995; 83: 109-119Crossref PubMed Scopus (105) Google Scholar 74Richards CD White AE The actions of volatile anaesthetics on synaptic transmission in the dentate gyrus.J Physiol. 1975; 252: 241-257Crossref PubMed Scopus (103) Google Scholar which has been attributed indirectly to a presynaptic mechanism, and decrease cortical neuron sensitivity to applied glutamate, a postsynaptic mechanism.45Minami K Wick MJ Stern-Bach Y et al.Sites of volatile anesthetic action on kainate (glutamate receptor 6) receptors.J Biol Chem. 1998; 273: 8248-8255Crossref PubMed Scopus (59) Google Scholar 73Richards CD Smaje JC Anaesthetics depress the sensitivity of cortical neurones to L-glutamate.Br J Pharmacol. 1976; 58: 347-357Crossref PubMed Scopus (111) Google Scholar 90Wakamori M Ikemoto Y Akaike N Effects of two volatile anesthetics and a volatile convulsant on the excitatory and inhibitory amino acid responses in dissociated CNS neurons of the rat.J Neurophysiol. 1991; 66: 2014-2021Crossref PubMed Scopus (0) Google Scholar 104Yang J Zorumski CF Effects of isoflurane on N-methyl-D-aspartate gated ion channels in cultured rat hippocampal neurons.Ann NY Acad Sci. 1991; 625: 287-289Crossref PubMed Scopus (75) Google Scholar General anaesthetics also decrease depolarization-induced glutamate release from brain slices,8Buggy DJ Nicol B Rowbotham DJ Lambert DG Effects of intravenous anesthetic agents on glutamate release: a role for GABAA receptor-mediated inhibition.Anesthesiology. 2000; 92: 1067-1073Crossref PubMed Scopus (83) Google Scholar 16Eilers H Kindler CH Bickler PE Different effects of volatile anesthetics and polyhalogenated alkanes on depolarization-evoked glutamate release in rat cortical brain slices.Anesth Analg. 1999; 88: 1168-1174Crossref PubMed Google Scholar 35Larsen M Grondahl TO Haugstad TS Langmoen IA The effect of the volatile anesthetic isoflurane on Ca2+-dependent glutamate release from rat cerebral cortex.Brain Res. 1994; 663: 335-337Crossref PubMed Scopus (45) Google Scholar 36Liachenko S Tang P Somogyi GT Xu Y Concentration-dependent isoflurane effects on depolarization-evoked glutamate and GABA outflows from mouse brain slices.Br J Pharmacol. 1999; 127: 131-138Crossref PubMed Scopus (32) Google Scholar but it is difficult to localize drug effects in such intact polysynaptic neuronal circuits. Volatile anaesthetics have limited effects on cloned α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or N-methyl-d-aspartic acid (NMDA) glutamate receptors but potentiate kainate receptors,13Dildy-Mayfield JE Eger III, E Harris RA Anesthetics produce subunit-selective actions on glutamate receptors.J Pharmacol Exp Ther. 1996; 276: 1058-1065PubMed Google Scholar 45Minami K Wick MJ Stern-Bach Y et al.Sites of volatile anesthetic action on kainate (glutamate receptor 6) receptors.J Biol Chem. 1998; 273: 8248-8255Crossref PubMed Scopus (59) Google Scholar consistent with a predominantly presynaptic mechanism for inhibition of glutamatergic synapses, although recent evidence suggests that NMDA receptor blockade could contribute to inhaled anaesthetic effects.12Dickinson R Peterson BK Banks P et al.Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor by the anesthetics xenon and isoflurane: evidence from molecular modeling and electrophysiology.Anesthesiology. 2007; 107: 756-767Crossref PubMed Scopus (187) Google Scholar 25Haseneder R Kratzer S Kochs E et al.Xenon reduces N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated synaptic transmission in the amygdala.Anesthesiology. 2008; 109: 998-1006Crossref PubMed Scopus (35) Google Scholar Most i.v. anaesthetics are remarkable for their relatively potent and selective potentiation of postsynaptic GABA responses.103Yamakura T Harris RA Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol.Anesthesiology. 2000; 93: 1095-1101Crossref PubMed Scopus (291) Google Scholar In contrast to glutamatergic synapses, augmentation of GABAergic responses by most general anaesthetics is mediated primarily by potentiation of postsynaptic and extrasynaptic GABAA receptors.27Hemmings Jr, HC Akabas MH Goldstein PA Trudell JR Orser BA Harrison NL Emerging molecular mechanisms of general anesthetic action.Trends Pharmacol Sci. 2005; 26: 503-510Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar Anaesthetics also have presynaptic effects at GABA terminals to increase IPSC frequency and GABA release,2Banks MI Pearce RA Dual actions of volatile anesthetics on GABA(A) IPSCs: dissociation of blocking and prolonging effects.Anesthesiology. 1999; 90: 120-134Crossref PubMed Scopus (156) Google Scholar 46Murugaiah KD Hemmings Jr, HC Effects of intravenous anesthetics on [3H]GABA release from rat cortical synaptosomes.Anesthesiology. 1998; 89: 919-928Crossref PubMed Scopus (44) Google Scholar 52Nishikawa K-I MacIver MB Excitatory synaptic transmission mediated by NMDA receptors is more sensitive to isoflurane than are non-NMDA receptor-mediated responses.Anesthesiology. 2000; 92: 228-236Crossref PubMed Scopus (97) Google Scholar 64Pittson S Himmel AM MacIver MB Multiple synaptic and membrane sites of anesthetic action in the CA1 region of rat hippocampal slices.BMC Neurosci. 2004; 5: 52Crossref PubMed Scopus (53) Google Scholar which combine with prolongation of action-potential-evoked IPSCs to increase inhibitory charge transfer and net inhibitory tone.6Bieda MC Maclver MB A major role for tonic GABAA conductances in anesthetic suppression of intrinsic neuronal excitability.J Neurophysiol. 2004; 92: 1658-1667Crossref PubMed Scopus (104) Google Scholar Investigations of the molecular targets responsible for these synaptic effects of general anaesthetics have focused on voltage-gated and ligand-gated ion channels, many of which have been cloned and are accessible to direct electrophysiological analysis.19Franks NP Lieb WR Molecular and cellular mechanisms of general anaesthesia.Nature. 1994; 367: 607-613Crossref PubMed Scopus (1613) Google Scholar 27Hemmings Jr, HC Akabas MH Goldstein PA Trudell JR Orser BA Harrison NL Emerging molecular mechanisms of general anesthetic action.Trends Pharmacol Sci. 2005; 26: 503-510Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar GABAA receptors in particular are potentiated by most general anaesthetics, which accounts for their postsynaptic actions on inhibitory synaptic transmission. Potentiation of GABAA receptors is clearly an important mechanism for i.v. anaesthetics such as propofol, the immobilizing effects of which can be antagonized by intrathecal injection of the GABAA receptor antagonist bicuculline6Bieda MC Maclver MB A major role for tonic GABAA conductances in anesthetic suppression of intrinsic neuronal excitability.J Neurophysiol. 2004; 92: 1658-1667Crossref PubMed Scopus (104) Google Scholar or by a β3 receptor N265M knock-in mutation in vivo.31Jurd R Arras M Lambert S et al.General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit.FASEB J. 2003; 17: 250-252Crossref PubMed Scopus (492) Google Scholar In contrast, potentiation of GABAA receptors is insufficient to explain the actions of volatile anaesthetics, since bicuculline does not antagonize immobilization by isoflurane.37Liao M Sonner JM Jurd R et al.Beta3-containing gamma-aminobutyric acidA receptors are not major targets for the amnesic and immobilizing actions of isoflurane.Anesth Analg. 2005; 101: 412-418Crossref PubMed Scopus (48) Google Scholar 107Zhang Y Sonner JM Eger EI II et al.Gamma-aminobutyric acidA receptors do not mediate the immobility produced by isoflurane.Anesth Analg. 2004; 99: 85-90Crossref PubMed Scopus (46) Google Scholar Thus volatile anaesthetic actions are less specific than those of most i.v. anaesthetics, and other sites of action must be involved. In addition to possible effects on glutamate receptors, convincing evidence exists for volatile anaesthetic effects on voltage-gated Na+ channels,54OuYang W Hemmings Jr, HC Depression by isoflurane of the action potential and underlying voltage-gated ion currents in isolated rat neurohypophysial nerve terminals.J Pharmacol Exp Ther. 2005; 312: 801-808Crossref PubMed Scopus (39) Google Scholar 58OuYang W Wang G Hemmings Jr, HC Isoflurane and propofol inhibit presynaptic Na+ channels in isolated rat neurohypophysial nerve terminals.Mol Pharmacol. 2003; 64: 373-381Crossref PubMed Scopus (81) Google Scholar 71Rehberg B Xiao Y-H Duch DS Central nervous system sodium channels are significantly suppressed at clinical concentrations of volatile anesthetics.Anesthesiology. 1996; 84: 1223-1233Crossref PubMed Scopus (129) Google Scholar 100Wu XS Sun JY Evers AS Crowder M Wu LG Isoflurane inhibits transmitter release and the presynaptic action potential.Anesthesiology. 2004; 100: 663-670Crossref PubMed Scopus (114) Google Scholar two-pore-domain background K+ (K2P) channels,18Franks NP Honoré E The TREK K2P channels and their role in general anaesthesia and neuroprotection.Trends Pharmacol Sci. 2004; 25: 601-608Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar 22Gray AT Zhao BB Kindler CH et al.Volatile anesthetics activate the human tandem pore domain baseline K+ channel KCNK5.Anesthesiology. 2000; 92: 1722-1730Crossref PubMed Scopus (76) Google Scholar 60Patel AJ Honoŕe E Lesage F Fink M Romey G Lazdunski M Inhalational anesthetics activate two-pore-domain background K+ channels.Nature Neurosci. 1999; 2: 422-426Crossref PubMed Scopus (558) Google Scholar nicotinic cholinergic receptors,17Flood P Ramirez-Latorre J Role L Alpha 4 beta 2 neuronal nicotinic acetylcholine receptors in the central nervous system are inhibited by isoflurane and propofol, but alpha 7-type nicotinic acetylcholine receptors are unaffected.Anesthesiology. 1997; 86: 859-865Crossref PubMed Scopus (229) Google Scholar 89Violet JM Downie DL Nakisa RC Lieb WR Franks NP Differential sensitivities of mammalian neuronal and muscle nicotinic acetylcholine receptors to general anesthetics.Anesthesiology. 1997; 86: 866-874Crossref PubMed Scopus (208) Google Scholar voltage-gated Ca2+ channels,32Kamatchi GL Chan CK Snutch T Durieux ME Lynch III, C Volatile anesthetic inhibition of neuronal Ca channel currents expressed in Xenopus oocytes.Brain Res. 1999; 831: 85-96Crossref PubMed Scopus (42) Google Scholar 50Nikonorov IM Blanck TJ Recio-Pinto E The effects of halothane on single human neuronal L-type calcium channels.Anesth Analg. 1998; 86: 885-895Crossref PubMed Google Scholar 84Study RE Isoflurane inhibits multiple voltage-gated Ca2+ currents in hippocampal pyramidal neurons.Anesthesiology. 1994; 81: 104-116Crossref PubMed Scopus (120) Google Scholar and presynaptic SNARE proteins.47Nagele P Mendel JB Placzek WJ Scott BA d’Avignon DA Crowder CM Volatile anesthetics bind rat synaptic SNARE proteins.Anesthesiology. 2005; 103: 768-778Crossref PubMed Scopus (33) Google Scholar An important goal is to identify the relevant molecular mechanisms for the presynaptic effects of volatile anaesthetics from among the multiple potential targets. The basic mechanisms underlying release are conserved among different neurotransmitters.86Südhof TC The synaptic vesicle cycle.Ann Rev Neurosci. 2004; 27: 509-547Crossref PubMed Scopus (1818) Google Scholar However, transmitter- and nerve-terminal-specific specializations exist, such as transmitter-specific involvement of individual Ca2+ channel types in release and the modulation of release by presynaptic receptors.39MacDermott AB Role LW Siegelbaum SA Presynaptic ionotropic receptors and the control of transm
Referência(s)