Key Points
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General anaesthetics are defined by their capacity to produce a state in which surgery can be tolerated without the need for further drugs. They are widely used in both clinical medicine and neuroscience research, but we are only just beginning to understand the molecular mechanisms that underlie their actions.
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The goals of the anaesthetic state are immobility, unconsciousness and amnesia. It is widely accepted that general anaesthetics cause immobility by depressing spinal neurons, and amnesia and hypnosis by acting on neurons in the brain. However, there is evidence that their spinal actions also influence sedative and hypnotic effects, and conversely, that descending signals from the brain to the spinal cord modify their immobilizing effects.
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There is a long list of molecular targets, the activity of which is mediated by at least one general anaesthetic, including numerous types of ligand-gated ion channel. In recent years, the GABAA (γ-aminobutyric acid type A) receptor system has attracted considerable attention as a target for general anaesthetics.
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The great heterogeneity of GABAA receptors has long precluded the attribution of physiological and pharmacological functions to specific subtypes. However, using knock-in point mutations in mice, it has been possible to identify specific GABAA-receptor subtypes that are involved in the actions of the intravenous anaesthetics etomidate and propofol.
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By integrating results from pharmacological, molecular genetic, functional imaging and electrophysiological studies, we should be able to gain further insights into the mechanisms of anaesthetic action. These insights might also provide avenues for the design of new general anaesthetics with an improved side-effect profile.
Abstract
Although general anaesthesia has been of tremendous importance for the development of surgery, the underlying mechanisms by which this state is achieved are only just beginning to be understood in detail. In this review, we describe the neuronal systems that are thought to be involved in mediating clinically relevant actions of general anaesthetics, and we go on to discuss how the function of individual drug targets, in particular GABAA-receptor subtypes, can be revealed by genetic studies in vivo.
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References
Fiset, P. et al. Brain mechanisms of propofol-induced loss of consciousness in humans: a positron emission tomographic study. J. Neurosci. 19, 5506–5513 (1999).
Steriade, M., Contreras, D. & Amzica, F. Synchronized sleep oscillations and their paroxysmal developments. Trends Neurosci. 17, 199–208 (1994).
Jefferys, J. G., Traub, R. D. & Whittington, M. A. Neuronal networks for induced '40 Hz' rhythms. Trends Neurosci. 19, 202–208 (1996).
Lukatch, H. S. & MacIver, M. B. Synaptic mechanisms of thiopental-induced alterations in synchronized cortical activity. Anesthesiology 84, 1425–1434 (1996).
Campagna, J. A., Miller, K. W. & Forman, S. A. Mechanisms of actions of inhaled anesthetics. N. Engl. J. Med. 348, 2110–2124 (2003).
Urban, B. W. & Bleckwenn, M. Concepts and correlations relevant to general anaesthesia. Br. J. Anaesth. 89, 3–16 (2002).
Sonner, J. M. et al. Inhaled anesthetics and immobility: mechanisms, mysteries, and minimum alveolar anesthetic concentration. Anesth. Analg. 97, 718–740 (2003).
Leake, C. D. Claude Bernard and anesthesia. Anesthesiology 35, 112–113 (1971).
Meyer, H. Welche eigenschaft der anästhetica bedingt ihre narkotische wirkung? Arch. Exp. Pathol. Pharmakol. (Naunyn-Schmiedeberg's) 42, 109–118 (1899).
Overton, E. Studien über die Narkose, zugleich ein Beitrag zur allgemeinen Pharmakologie (Gustav Fischer, Jena, 1901).
Franks, N. P. & Lieb, W. R. Do general anaesthetics act by competitive binding to specific receptors? Nature 310, 599–601 (1984). This classic paper shows that general anaesthetics inhibit a water-soluble protein (firefly luciferase). Effects occur at clinically relevant concentrations and follow the Meyer–Overton rule.
Franks, N. P. & Lieb, W. R. Molecular and cellular mechanisms of general anaesthesia. Nature 367, 607–614 (1994).
Franks, N. P. & Lieb, W. R. Molecular mechanisms of general anaesthesia. Nature 300, 487–493 (1982).
Koblin, D. D. et al. Polyhalogenated and perfluorinated compounds that disobey the Meyer-Overton hypothesis. Anesth. Analg. 79, 1043–1048 (1994).
Franks, N. P. & Lieb, W. R. Where do general anaesthetics act? Nature 274, 339–342 (1978).
Raines, D. E., Korten, S. E., Hill, A. G. & Miller, K. W. Anesthetic cutoff in cycloalkanemethanols. A test of current theories. Anesthesiology 78, 918–927 (1993).
Antognini, J. F. & Carstens, E. In vivo characterization of clinical anaesthesia and its components. Br. J. Anaesth. 89, 156–166 (2002).
Kendig, J. J. Spinal cord as a site of anesthetic action. Anesthesiology 79, 1161–1162 (1993).
Eger, E. I. et al. Hypothesis: inhaled anesthetics produce immobility and amnesia by different mechanisms at different sites. Anesth. Analg. 84, 915–918 (1997).
Kissin, I. A concept for assessing interactions of general anesthetics. Anesth. Analg. 85, 204–210 (1997).
Veselis, R. A., Reinsel, R. A., Feshchenko, V. A. & Dnistrian, A. M. A neuroanatomical construct for the amnesic effects of propofol. Anesthesiology 97, 329–337 (2002).
Smith, C. et al. The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision. Anesthesiology 81, 820–828 (1994).
Nelson, L. E. et al. The sedative component of anesthesia is mediated by GABAA receptors in an endogenous sleep pathway. Nature Neurosci. 5, 979–984 (2002). The GABA antagonist gabazine was shown to attenuate the sedative response to GABA-containing agents when injected locally into the tuberomamillary nucleus, indicating that a discrete locus has a key role in the sedative response to anaesthetics that affect GABA-mediated neurotransmission.
Alkire, M. T. & Haier, R. J. Correlating in vivo anaesthetic effects with ex vivo receptor density data supports a GABAergic mechanism of action for propofol, but not for isoflurane. Br. J. Anaesth. 86, 618–626 (2001).
Gyulai, F. E., Mintun, M. A. & Firestone, L. L. Dose-dependent enhancement of in vivo GABAA-benzodiazepine receptor binding by isoflurane. Anesthesiology 95, 585–593 (2001).
Alkire, M. T. Quantitative EEG correlations with brain glucose metabolic rate during anesthesia in volunteers. Anesthesiology 89, 323–333 (1998).
Veselis, R. A. et al. Midazolam changes cerebral blood flow in discrete brain regions: an H215O positron emission tomography study. Anesthesiology 87, 1106–1117 (1997).
Gugino, L. D. et al. Quantitative EEG changes associated with loss and return of consciousness in healthy adult volunteers anaesthetized with propofol or sevoflurane. Br. J. Anaesth. 87, 421–428 (2001).
Alkire, M. T., Haier, R. J. & Fallon, J. H. Toward a unified theory of narcosis: brain imaging evidence for a thalamocortical switch as the neurophysiologic basis of anesthetic-induced unconsciousness. Conscious Cogn. 9, 370–386 (2000).
Steriade, M. Arousal: revisiting the reticular activating system. Science 272, 225–226 (1996).
Hofbauer, R. K., Fiset, P., Plourde, G., Backman, S. B. & Bushnell, M. C. Dose-dependent effects of propofol on the central processing of thermal pain. Anesthesiology 100, 386–394 (2004). Provides clear evidence that loss of consciousness and pain sensation correlates with propofol-induced interruption of thalamic information processing.
Bonhomme, V. et al. Propofol anesthesia and cerebral blood flow changes elicited by vibrotactile stimulation: a positron emission tomography study. J. Neurophysiol. 85, 1299–1308 (2001).
Kochs, E., Stockmanns, G., Thornton, C., Nahm, W. & Kalkman, C. J. Wavelet analysis of middle latency auditory evoked responses: calculation of an index for detection of awareness during propofol administration. Anesthesiology 95, 1141–1150 (2001).
Moruzzi, G. & Magoun, H. W. Brain stem reticular formation and activation of the EEG. Electroencaphalogr. Clin. Neurophysiol. 1, 455–473 (1949).
Ogawa, T., Shingu, K., Shibata, M., Osawa, M. & Mori, K. The divergent actions of volatile anaesthetics on background neuronal activity and reactive capability in the central nervous system in cats. Can. J. Anaesth. 39, 862–872 (1992).
Keifer, J. C., Baghdoyan, H. A. & Lydic, R. Pontine cholinergic mechanisms modulate the cortical electroencephalographic spindles of halothane anesthesia. Anesthesiology 84, 945–954 (1996).
Perry, E., Walker, M., Grace, J. & Perry, R. Acetylcholine in mind: a neurotransmitter correlate of consciousness? Trends Neurosci. 22, 273–280 (1999).
Tung, A., Bergmann, B. M., Herrera, S., Cao, D. & Mendelson, W. B. Recovery from sleep deprivation occurs during propofol anesthesia. Anesthesiology 100, 1419–1426 (2004).
Cariani, P. Anesthesia, neural information processing, and conscious awareness. Conscious Cogn. 9, 387–395 (2000).
Mashour, G. A. Consciousness unbound: toward a paradigm of general anesthesia. Anesthesiology 100, 428–433 (2004).
Langsjo, J. W. et al. Effects of subanesthetic doses of ketamine on regional cerebral blood flow, oxygen consumption, and blood volume in humans. Anesthesiology 99, 614–623 (2003).
Moghaddam, B., Adams, B., Verma, A. & Daly, D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J. Neurosci. 17, 2921–2927 (1997).
Schwender, D., Klasing, S., Madler, C., Poppel, E. & Peter, K. Mid-latency auditory evoked potentials during ketamine anaesthesia in humans. Br. J. Anaesth. 71, 629–632 (1993).
Garfield, J. M., Garfield, F. B., Stone, J. B., Hopkins, D. & Johns, L. A. A comparison of psychologic responses to ketamine and thiopental-nitrous oxide-halothane anesthesia. Anesthesiology 36, 329–338 (1972).
Singer, W. & Gray, C. M. Visual feature integration and the temporal correlation hypothesis. Annu. Rev. Neurosci. 18, 555–586 (1995).
John, E. R. et al. Invariant reversible QEEG effects of anesthetics. Conscious Cogn. 10, 165–183 (2001).
Dickinson, R., Awaiz, S., Whittington, M. A., Lieb, W. R. & Franks, N. P. The effects of general anaesthetics on carbachol-evoked γ-oscillations in the rat hippocampus in vitro. Neuropharmacology 44, 864–872 (2003).
Antkowiak, B. Different actions of general anesthetics on the firing patterns of neocortical neurons mediated by the GABAA receptor. Anesthesiology 91, 500–511 (1999).
Kaisti, K. K. et al. Effects of surgical levels of propofol and sevoflurane anesthesia on cerebral blood flow in healthy subjects studied with positron emission tomography. Anesthesiology 96, 1358–1370 (2002).
Heinke, W. et al. Sequential effects of propofol on functional brain activation induced by auditory language processing: an event-related functional magnetic resonance imaging study. Br. J. Anaesth. 92, 641–650 (2004).
Heinke, W. & Schwarzbauer, C. Subanesthetic isoflurane affects task-induced brain activation in a highly specific manner: a functional magnetic resonance imaging study. Anesthesiology 94, 973–981 (2001). Reports that higher-level cortical information processing is more sensitive to anaesthetic treatment than sensory processing in primary cortices and subcortical structures.
Logothetis, N. K., Guggenberger, H., Peled, S. & Pauls, J. Functional imaging of the monkey brain. Nature Neurosci. 2, 555–562 (1999).
Pack, C. C., Berezovskii, V. K. & Born, R. T. Dynamic properties of neurons in cortical area MT in alert and anaesthetized macaque monkeys. Nature 414, 905–908 (2001).
Antognini, J. F., Wang, X. W., Piercy, M. & Carstens, E. Propofol directly depresses lumbar dorsal horn neuronal responses to noxious stimulation in goats. Can. J. Anaesth. 47, 273–279 (2000).
Rampil, I. J., Mason, P. & Singh, H. Anesthetic potency (MAC) is independent of forebrain structures in the rat. Anesthesiology 78, 707–712 (1993). Pre-collicular decerebration in rats does not affect their sensitivity to the immobilizing action of isoflurane, indicating that anaesthetic-induced unresponsiveness to noxious stimuli does not depend on cortical or forebrain structures in the rat.
Rampil, I. J. Anesthetic potency is not altered after hypothermic spinal cord transection in rats. Anesthesiology 80, 606–610 (1994). After cervical laminectomy and hypothermic spinal cord transsection, the sensitivity to the immobilizing action of isoflurane was not changed, despite acute loss of descending supraspinal controls. So, the site of anaesthetic inhibition of motor response is probably in the spinal cord.
Antognini, J. F. & Schwartz, K. Exaggerated anesthetic requirements in the preferentially anesthetized brain. Anesthesiology 79, 1244–1249 (1993). In goats, delivery of anaesthetic drugs specifically to the brain, compared with delivery to the spinal cord, increased the concentration that is needed to suppress noxious-stimuli-induced movements three–fourfold.
Zhou, H. H., Jin, T. T., Qin, B. & Turndorf, H. Suppression of spinal cord motoneuron excitability correlates with surgical immobility during isoflurane anesthesia. Anesthesiology 88, 955–961 (1998).
Antognini, J. F., Wang, X. W. & Carstens, E. Isoflurane action in the spinal cord blunts electroencephalographic and thalamic-reticular formation responses to noxious stimulation in goats. Anesthesiology 92, 559–566 (2000).
Ma, J., Shen, B., Stewart, L. S., Herrick, I. A. & Leung, L. S. The septohippocampal system participates in general anesthesia. J. Neurosci. 22, RC200 (2002).
Merkel, G. & Eger, E. I. A comparative study of halothane and halopropane anesthesia including method for determining equipotency. Anesthesiology 24, 346–357 (1963).
Jinks, S. L., Martin, J. T., Carstens, E., Jung, S. W. & Antognini, J. F. Peri-MAC depression of a nociceptive withdrawal reflex is accompanied by reduced dorsal horn activity with halothane but not isoflurane. Anesthesiology 98, 1128–1138 (2003).
Zhang, Y. et al. γ-aminobutyric acidA receptors do not mediate the immobility produced by isoflurane. Anesth. Analg. 99, 85–90 (2004).
Yamakura, T., Bertaccini, E., Trudell, J. R. & Harris, R. A. Anesthetics and ion channels: molecular models and sites of action. Annu. Rev. Pharmacol. Toxicol. 41, 23–51 (2001).
Patel, A. J. & Honoré, E. Anesthetic-sensitive 2P domain K+ channels. Anesthesiology 95, 1013–1021 (2001).
Jurd, R. et al. General anesthetic actions in vivo strongly attenuated by a point mutation in the GABAA receptor β3 subunit. FASEB J. 17, 250–252 (2003). Describes the generation and analysis of β3(N265M) knock-in mice, which have etomidate- and propofol-insensitive β3-containing GABA A receptors. In these mice, the duration of the loss of the righting reflex (hypnotic response) to etomidate and propofol was substantially decreased, and the hindlimb-withdrawal reflex (immobilizing response) was not lost in response to etomidate, indicating an involvement of β3-containing GABA A receptors in these responses.
Reynolds, D. S. et al. Sedation and anesthesia mediated by distinct GABAA receptor isoforms. J. Neurosci. 23, 8608–8617 (2003). Describes the generation and analysis of β2(N265S) knock-in mice, which have largly etomidate- but not propofol-insensitive β2-containing GABA A receptors. The hypnotic and immobilizing responses to etomidate were still present, but the sedation that is usually induced by subanaesthetic doses of etomidate was absent. So, β2-containing GABA A receptors mediate the sedative action of etomidate.
McKernan, R. M. & Whiting, P. J. Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci. 19, 139–143 (1996).
Möhler, H., Fritschy, J. M. & Rudolph, U. A new benzodiazepine pharmacology. J. Pharmacol. Exp. Ther. 300, 2–8 (2002).
Wallner, M., Hanchar, H. J. & Olsen, R. W. Ethanol enhances α4β3δ and α6β3δ γ-aminobutyric acid type A receptors at low concentrations known to affect humans. Proc. Natl Acad. Sci. USA 100, 15218–15223 (2003).
Wisden, W., Laurie, D. J., Monyer, H. & Seeburg, P. H. The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J. Neurosci. 12, 1040–1062 (1992).
Laurie, D. J., Seeburg, P. H. & Wisden, W. The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum. J. Neurosci. 12, 1063–1076 (1992).
Fritschy, J. M. & Möhler, H. GABAA-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J. Comp. Neurol. 359, 154–194 (1995).
Fritschy, J. M. & Brünig, I. Formation and plasticity of GABAergic synapses: physiological mechanisms and pathophysiological implications. Pharmacol. Ther. 98, 299–323 (2003).
Rudolph, U. & Mühler, H. Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annu. Rev. Pharmacol. Toxicol. 44, 475–498 (2004).
Mihalek, R. M. et al. Attenuated sensitivity to neuroactive steroids in γ-aminobutyrate type A receptor δ-subunit knockout mice. Proc. Natl Acad. Sci. USA 96, 12905–12910 (1999).
Quinlan, J. J., Homanics, G. E. & Firestone, L. L. Anesthesia sensitivity in mice that lack the β3 subunit of the γ-aminobutyric acid type A receptor. Anesthesiology 88, 775–780 (1998). Provides the first report on responses to general anaesthetics being altered by the knockout of a GABA A -receptor subunit.
Wong, S. M., Cheng, G., Homanics, G. E. & Kendig, J. J. Enflurane actions on spinal cords from mice that lack the β3 subunit of the GABAA receptor. Anesthesiology 95, 154–164 (2001).
Mihic, S. J. et al. Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors. Nature 389, 385–389 (1997). In this elegant study, sites relevant for the action of general anaesthetics on Gly- and GABA A -receptor subunits near the transmembrane domains 2 and 3 have been identified.
Belelli, D., Lambert, J. J., Peters, J. A., Wafford, K. & Whiting, P. J. The interaction of the general anesthetic etomidate with the γ-aminobutyric acid type A receptor is influenced by a single amino acid. Proc. Natl Acad. Sci. USA 94, 11031–11036 (1997). Identification of amino-acid residues in the β-subunits that render GABA A receptors etomidate-sensitive or insensitive. This electrophysiological study on recombinant receptors is the basis for the development of the β2(N265S) and β3(N265M) mouse models.
Krasowski, M. D. et al. Propofol and other intravenous anesthetics have sites of action on the γ-aminobutyric acid type A receptor distinct from that for isoflurane. Mol. Pharmacol. 53, 530–538 (1998).
Pistis, M., Belelli, D., McGurk, K., Peters, J. A. & Lambert, J. J. Complementary regulation of anaesthetic activation of human (α6β3γ2L) and Drosophila (RDL) GABA receptors by a single amino acid residue. J. Physiol. 515, 3–18 (1999).
Siegwart, R., Jurd, R. & Rudolph, U. Molecular determinants for the action of general anesthetics at recombinant α2β3γ2 γ-aminobutyric acidA receptors. J. Neurochem. 80, 140–148 (2002).
Siegwart, R., Krähenbühl, K., Lambert, S. & Rudolph, U. Mutational analysis of molecular requirements for the actions of general anaesthetics at the γ-aminobutyric acidA receptor subtype, α1β2γ2. BMC Pharmacol. 3, 13 (2003).
Husain, S. S. et al. 2-(3-Methyl-3H-diaziren-3-yl)ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate: a derivative of the stereoselective general anesthetic etomidate for photolabeling ligand-gated ion channels. J. Med. Chem. 46, 1257–1265 (2003).
Fagiolini, M. et al. Specific GABAA circuits for visual cortical plasticity. Science 303, 1681–1683 (2004).
Rudolph, U. et al. Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes. Nature 401, 796–800 (1999). The first description of α1(H101R) knock-in mice, which have diazepam-insensitive α1-containing GABA A receptors. In these mice, the sedative, anterograde amnesic and in part the anticonvulsant actions of diazepam were absent, whereas the anxiolytic-like, muscle relaxant, motor-impairing and ethanol-potentiating actions were present, demonstrating the GABA A -receptor subtype-specificity of diazepam action.
McKernan, R. M. et al. Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype. Nature Neurosci. 3, 587–592 (2000). This paper also reports on the generation and analysis of α1(H101R) knock-in mice. In addition, L-838,417, which is a partial agonist at α2-, α3-, α5- but not α1-containing GABA A receptors, is reported to be anxiolytic in rats.
Löw, K. et al. Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290, 131–134 (2000).
Crestani, F. et al. Molecular targets for the myorelaxant action of diazepam. Mol. Pharmacol. 59, 442–445 (2001).
Crestani, F. et al. Trace fear conditioning involves hippocampal α5 GABAA receptors. Proc. Natl Acad. Sci. USA 99, 8980–8985 (2002).
Kralic, J. E. et al. GABAA receptor α1 subunit deletion alters receptor subtype assembly, pharmacological and behavioral responses to benzodiazepines and zolpidem. Neuropharmacology 43, 685–694 (2002).
Reynolds, D. S. et al. GABAA α1 subunit knock-out mice do not show a hyperlocomotor response following amphetamine or cocaine treatment. Neuropharmacology 44, 190–198 (2003).
Nishikawa, K., Jenkins, A., Paraskevakis, I. & Harrison, N. L. Volatile anesthetic actions on the GABAA receptors: contrasting effects of α1(S270) and β2(N265) point mutations. Neuropharmacology 42, 337–345 (2002).
Engelhardt, D. & Weber, M. M. Therapy of Cushing's syndrome with steroid biosynthesis inhibitors. J. Steroid Biochem. Mol. Biol. 49, 261–267 (1994).
Paris, A. et al. Activation of α2B-adrenoceptors mediates the cardiovascular effects of etomidate. Anesthesiology 99, 889–895 (2003).
Sallinen, J., Haapalinna, A., Viitamaa, T., Kobilka, B. K. & Scheinin, M. Adrenergic α2C-receptors modulate the acoustic startle reflex, prepulse inhibition, and aggression in mice. J. Neurosci. 18, 3035–3042 (1998).
Lakhlani, P. P. et al. Substitution of a mutant α2a-adrenergic receptor via 'hit and run' gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo. Proc. Natl Acad. Sci. USA 94, 9950–9955 (1997).
Hill-Venning, C., Belelli, D., Peters, J. A. & Lambert, J. J. Subunit-dependent interaction of the general anaesthetic etomidate with the γ-aminobutyric acid type A receptor. Br. J. Pharmacol. 120, 749–756 (1997).
Sanna, E. et al. Actions of the general anesthetic propofol on recombinant human GABAA receptors: influence of receptor subunits. J. Pharmacol. Exp. Ther. 274, 353–360 (1995).
Hill-Venning, C. et al. The anaesthetic action and modulation of GABAA receptor activity by the novel water-soluble aminosteroid Org 20599. Neuropharmacology 35, 1209–1222 (1996).
Pistis, M., Belelli, D., Peters, J. A. & Lambert, J. J. The interaction of general anaesthetics with recombinant GABAA and glycine receptors expressed in Xenopus laevis oocytes: a comparative study. Br. J. Pharmacol. 122, 1707–1719 (1997).
Friederich, P. & Urban, B. W. Interaction of intravenous anesthetics with human neuronal potassium currents in relation to clinical concentrations. Anesthesiology 91, 1853–1860 (1999).
Lingamaneni, R., Birch, M. L. & Hemmings, H. C. Widespread inhibition of sodium channel-dependent glutamate release from isolated nerve terminals by isoflurane and propofol. Anesthesiology 95, 1460–1466 (2001).
Lingamaneni, R. & Hemmings, H. C. Differential interaction of anaesthetics and antiepileptic drugs with neuronal Na+ channels, Ca2+ channels, and GABAA receptors. Br. J. Anaesth. 90, 199–211 (2003).
Guertin, P. A. & Hounsgaard, J. Non-volatile general anaesthetics reduce spinal activity by suppressing plateau potentials. Neuroscience 88, 353–358 (1999).
Krasowski, M. D. & Harrison, N. L. General anaesthetic actions on ligand-gated ion channels. Cell. Mol. Life Sci. 55, 1278–1303 (1999).
Antognini, J. F., Saadi, J., Wang, X. W., Carstens, E. & Piercy, M. Propofol action in both spinal cord and brain blunts electroencephalographic responses to noxious stimulation in goats. Sleep 24, 26–31 (2001).
Cirone, J. et al. γ-aminobutyric acid type A receptor β2 subunit mediates the hypothermic effect of etomidate in mice. Anesthesiology 100, 1438–1445 (2004).
Yamakura, T. & Harris, R. A. Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol. Anesthesiology 93, 1095–1101 (2000).
Dzoljic, M. & Van Duijn, B. Nitrous oxide-induced enhancement of γ-aminobutyric acidA-mediated chloride currents in acutely dissociated hippocampal neurons. Anesthesiology 88, 473–480 (1998).
Hapfelmeier, G., Zieglgansberger, W., Haseneder, R., Schneck, H. & Kochs, E. Nitrous oxide and xenon increase the efficacy of GABA at recombinant mammalian GABAA receptors. Anesth. Analg. 91, 1542–1549 (2000).
Mennerick, S. et al. Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures. J. Neurosci. 18, 9716–9726 (1998).
Jevtovic-Todorovic, V. et al. Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nature Med. 4, 460–463 (1998).
Kammer, T. et al. Propofol and sevoflurane in subanesthetic concentrations act preferentially on the spinal cord: evidence from multimodal electrophysiological assessment. Anesthesiology 97, 1416–1425 (2002).
Grasshoff, C. & Antkowiak, B. Propofol and sevoflurane depress spinal neurons in vitro via different molecular targets. Anesthesiology (in the press).
Urban, B. W. Current assessment of targets and theories of anaesthesia. Br. J. Anaesth. 89, 167–183 (2002).
Martin, J. H. Neuroanatomy: Text and Atlas 2nd edn (Appleton & Lange, Connecticut, 1996).
Acknowledgements
The authors would like to acknowledge the dedicated work of R. Jurd, M. Arras, S. Lambert and others on the β3(N265M) mouse model discussed in this review. The work was supported by the Swiss National Science Foundation (U.R.), the Deutsche Forschungsgemeinschaft (B.A.) and the Interdisciplinary Center for Clinical Research (IZKF) Tübingen (B.A.).
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Glossary
- BENZODIAZEPINES
-
Pharmacologically active molecules with sedative, anxiolytic and anticonvulsant effects. They act by binding to the GABA receptor and potentiate the response elicited by the transmitter.
- OPTICAL ISOMERS
-
Also known as chiral molecules, optical isomers are molecules that are exact non-superimposable mirror images of one another.
- ELECTROENCEPHALOGRAPHY
-
(EEG). A technique used to measure neural activity by monitoring electrical signals from the brain that reach the scalp. EEG has good temporal resolution but relatively poor spatial resolution.
- ALPHA POWER
-
Rhythmic neural activity with a frequency of 8–12 Hz.
- BETA POWER
-
Rhythmic neural activity with a frequency of 12–25 Hz.
- THETA POWER
-
Rhythmic neural activity with a frequency of 4–12 Hz.
- DELTA POWER
-
Rhythmic neural activity with a frequency of 1–4 Hz that is characteristic of stage III and IV non-rapid eye movement sleep (also known as slow-wave sleep).
- TONIC
-
Physiological events that occur in a sustained manner, unlike phasic events, which occur only transiently with intervening periods of inactivity.
- GAMMA OSCILLATIONS
-
Rhythmic neural activity with a frequency of 25–70 Hz.
- EC50
-
The concentration of an agent that provides a half-maximal activation of a target in vitro.
- IC50
-
The concentration of an agent that provides a half-maximal inhibition of a target in vitro.
- TAIL CLAMP/WITHDRAWAL ASSAY
-
An assay in which motor activity is measured in response to a tail-clamp stimulus.
- KNOCK-IN TRANSGENIC APPROACH
-
The insertion of a mutant gene at the exact site of the genome where the corresponding wild-type gene is located. This approach is used to ensure that the effect of the mutant gene is not affected by the activity of the endogenous locus.
- PRE-PULSE INHIBITION
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The ability of a weak pre-stimulus to inhibit the response to a stronger stimulus when the two stimuli are presented in quick succession.
- TETRODOTOXIN
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A potent marine neurotoxin that blocks voltage-gated sodium channels. Tetrodotoxin was originally isolated from the tetraodon pufferfish, and contains a positively charged guanidinium group and a pyrimidine ring.
- PLATEAU POTENTIAL
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A stable membrane potential that is more depolarized than the resting potential. The term derives from the 'plateau phase' of the action potential.
- HINDLIMB-WITHDRAWAL REFLEX
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If a mouse's hindlimbs are pulled back, the animal finds this painful, and it reflexively draws the limbs in towards the body.
- PURKINJE CELLS
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Inhibitory neurons in the cerebellum that use GABA as their neurotransmitter. Their cell bodies are situated beneath the molecular layer, and their dendrites branch extensively in this layer. Their axons project into the underlying white matter, and they provide the only output from the cerebellar cortex.
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Rudolph, U., Antkowiak, B. Molecular and neuronal substrates for general anaesthetics. Nat Rev Neurosci 5, 709–720 (2004). https://doi.org/10.1038/nrn1496
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DOI: https://doi.org/10.1038/nrn1496
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