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W2077993124 abstract "Although they affect many different organ systems within the body, general anaesthetics are administered primarily to render patients unconscious during surgical procedures. While unconscious, patients do not experience pain and the events surrounding the surgery are largely forgotten. As the brain and spinal cord are the organs that give rise to our individual and personal perceptions of the world, they are clearly the sites at which general anaesthetics exert their chief actions. Immobility, the other desirable characteristic of anaesthesia, is nowadays usually achieved by the use of muscle relaxants, which block neuromuscular transmission. It is an unfortunate fact that, whereas the pathways that are responsible for many important reflexes are now relatively well understood, those that are involved in the emergent properties of central nervous system (CNS) function (i.e. consciousness and perception) are much less well defined. Although spinal pathways are involved both in reflex behaviour (such as limb flexion in response to a nociceptive stimulus) and in the transmission of information about the state of the body to the brain, it is the brain that is responsible for the formation of perceptions about the world and the setting down of memory. Therefore, to understand fully how general anaesthetics work, it will be necessary to understand the neural mechanisms that underlie consciousness. This is a difficult problem and it may appear from this analysis that any attempt to elucidate the mechanisms involved in general anaesthesia is unlikely to succeed. However, as with many troublesome issues, a reductionist approach provides a useful starting point. The changes that are responsible for the state we call general anaesthesia must ultimately be an expression of the activity of the neurones that make up the nervous system. This activity depends both on the excitability of the constituent neurones and on their synaptic physiology. For this reason, much effort has been devoted to understanding how anaesthetics modulate synaptic transmission in defined neural pathways. This review, which is an update of an earlier one on the same topic,73Pocock G Richards CD Excitatory and inhibitory synaptic mechanisms in anaesthesia.Br J Anaesth. 1993; 71: 134-147Crossref PubMed Scopus (110) Google Scholar will explore the mechanisms that underlie these effects. It will present evidence that anaesthetics act mainly by modulating synaptic transmission. These effects are the result of actions on a small number of different types of ion channel, notably ligand-gated channels. Since the original description of synaptic transmission by Sherrington84Sherrington CS The Integrative Action of the Nervous System. Yale University Press, New Haven1906Google Scholar in the early part of the last century, the detailed mechanisms that underpin synaptic transmission have gradually become clearer. In mammals, including man, synapses generally operate by the secretion of a small quantity of a chemical (a neurotransmitter) from the nerve terminal. Such synapses are known as chemical synapses. However, some synapses operate by passing the electrical current generated by the action potential to the postsynaptic cell via gap junctions between adjacent neurones (electrical synaptic transmission). This type of synaptic transmission is not found in mammals but is important in some invertebrates, for example crayfish.36Furshpan EJ Potter DD Transmission at the giant synapses of the crayfish.J Physiol (Lond). 1959; 145: 289-325Crossref Scopus (465) Google Scholar Nevertheless, gap junctions between adjacent neurones do occur in some areas of the mammalian CNS, although their precise function remains unknown in most cases. Gap junctions do not exhibit the directional transmission characteristic of chemical synapses. A well-known example of gap junction connections between neurones is the coupling between the horizontal cells of the retina, which facilitates the lateral spread of activity between the dendrites of adjacent neurones.11Borst A Engelhaaf M Dendritic processing of synaptic information by sensory interneurons.Trends Neurosci. 1994; 17: 257-263Abstract Full Text PDF PubMed Scopus (36) Google Scholar As the wider importance of electrical synapses in the activity of the mammalian CNS is uncertain, the action of anaesthetics on this mode of synaptic transmission will not be discussed further. Before proceeding, it may be helpful to remind the reader of the basic organization of neurones. Their cell bodies are very varied in both size and shape but all CNS neurones have extensive branches called dendrites, which receive information from many other neurones. Each nerve cell gives rise to a single axon, which subsequently branches to contact a number of different target cells. The axon branches are called collaterals. As they make contact with other neurones they form synapses, which act as one-way valves for the passage of information from one neurone to another. An axon may form a synaptic contact with a dendrite, a cell body or another axon. Occasionally, synapses are formed between two dendrites (dendrodendritic synapses), as in the nigrostriatal pathway.41Groves PM Linder JC Dendro-dendritic synapses in substantia nigra: descriptions based on analysis of serial sections.Exp Brain Res. 1983; 49: 209-217Crossref PubMed Scopus (92) Google Scholar When axons reach their target cells, they form small swellings known as synaptic boutons. In the CNS, a single axon frequently makes contact with a number of target neurones as it courses though the tissue. Such synapses are known as en passage synapses, and similar synaptic contacts also occur between autonomic nerves and their target cells (Fig. 1).69Peters A Palay SL Webster HD The Fine Structure of the Nervous System: Neurons and Their Supporting Cells. 3rd edn. Oxford University Press, New York1991Google Scholar In other cases, an axon branch ends in a small swelling called a nerve terminal, which contacts its target cell. The classical example of this type of synaptic contact is the neuromuscular junction.9Birks R Huxley HE Katz B The fine structure of the neuromuscular junction of the frog.J Physiol (Lond). 1960; 150: 134-144Crossref Scopus (203) Google Scholar In this account, the terms ‘synaptic bouton’ and ‘nerve terminal’ will be used interchangeably as the functions of these contacts are identical (although their properties may differ in detail). The synaptic bouton, or nerve terminal, together with the underlying membrane on the target cell, constitutes a synapse. The nerve terminal is the presynaptic component of the synapse and is usually closely attached to the target (or postsynaptic) cell, leaving only a small gap of about 20 nm between the two elements. This small gap is known as the synaptic cleft, and it isolates electrically the presynaptic and postsynaptic cells. The nerve terminals contain mitochondria, cytoskeletal elements and a large number of small vesicles known as synaptic vesicles (Fig. 1). Under the electron microscope these may appear either as small, round, membrane-delimited features lacking any electron-dense material in their centre (as is the case for the majority of synaptic contacts in the CNS) or they may contain electron-dense material of some kind.57Lundberg JM Hokfelt T Coexistence of peptides and classical neurotransmitters.Trends Neurosci. 1983; 6: 325-332Abstract Full Text PDF Scopus (467) Google Scholar Vesicles of the latter type are referred to as dense-cored vesicles and are found typically on the noradrenergic nerve fibres of the sympathetic nervous system. The membrane immediately under the nerve terminal is called the postsynaptic membrane; it often contains electron-dense material that makes it appear thicker than that of the plasma membrane outside the synaptic region. This is known as the postsynaptic thickening. The postsynaptic membrane contains specific receptor molecules for the neurotransmitter released by the nerve terminal. The principal events during the operation of a chemical synapse are as follows. Action potentials travel along the axon of the presynaptic neurone and invade the synaptic boutons, which become depolarized. This depolarization opens voltage-gated calcium channels, allowing calcium ions to enter the nerve terminal. The consequent increase in the free calcium concentration triggers the secretion of a neurotransmitter (such as acetylcholine, glutamate or GABA) from the nerve terminal into the synaptic cleft. This process occurs via the fusion of a synaptic vesicle with the presynaptic membrane of the bouton, during which the contents of one or more vesicles become discharged into the synaptic cleft (exocytosis). The neurotransmitter diffuses across the synaptic cleft and binds to specific receptor molecules on the postsynaptic membrane. As a result, ion channels open and change the permeability of the postsynaptic membrane, so modulating the excitability of the postsynaptic neurone (Fig. 2). For many synapses within the CNS, the link between the arrival of an action potential at a bouton and the secretion of neurotransmitter is probabilistic. Thus, the action potential increases the probability that a synaptic vesicle will empty its contents into the synaptic cleft, but not every action potential will result in the secretion of neurotransmitter (i.e. the probability of vesicle release is less than 1). This interpretation is an extension of the classical work of Bernard Katz and his colleagues on synaptic transmission at the neuromuscular junction.47Katz B The Release of Neural Transmitter Substances. Liverpool University Press, Liverpool1969Google Scholar Confocal imaging of small projections on dendrites, known as dendritic spines, has recently provided direct evidence of the probabilistic nature of transmitter release in the CNS32Emptage N Bliss TV Fine A Single synaptic events evoke NMDA receptor-mediated release of calcium from internal stores in hippocampal dendritic spines.Neuron. 1999; 22: 115-124Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar and legitimizes the use of probabilistic analysis of synaptic transmission at visually identified CNS synapses. (This powerful analytical tool is often called quantal analysis.) Action potentials in the presynaptic neurone may lead to excitation or inhibition of the postsynaptic cells according to the type of synaptic contact. If the transmitter activates an ion channel directly, synaptic transmission is usually both rapid and short-lived. This type of transmission is called fast synaptic transmission and is typified by the action of acetylcholine at the neuromuscular junction. If the neurotransmitter activates a G-protein-linked receptor, the change in the postsynaptic cell is much slower in onset and lasts for a much greater period. An example is the excitatory action of norepinephrine on α1-adrenoceptors in the peripheral blood vessels. The secreted neurotransmitter is removed from the synaptic cleft by diffusion, by enzymatic activity or by uptake into the nerve terminals of surrounding glial cells. From this bare outline, it is clear that synaptic transmission can be divided into two main stages'a presynaptic stage, which is concerned with the mechanisms involved in controlling the secretion of the neurotransmitter, and a postsynaptic stage, which is concerned with the processes that occur in the postsynaptic cell after the secreted neurotransmitter has bound to its receptor. To understand precisely how general anaesthetics modulate the activity of the CNS, it is necessary to answer the following questions. First and foremost, do anaesthetics affect synaptic transmission or do they modulate the excitability of the neurones themselves? If they affect synaptic transmission, are their main effects presynaptic or postsynaptic? If their action is presynaptic, what is the mechanism? Do they interfere with action potential propagation into the presynaptic nerve fibres? If so, is the mechanism responsible for this effect a partial blockade of voltage-gated sodium channels or an increase in potassium conductance in the resting membrane? Alternatively, do anaesthetics reduce the probability of transmitter release? If so, do they act by reducing the amplitude of the calcium transients in the presynaptic nerve terminals or do they have a direct effect on the cellular apparatus responsible for the secretion of neurotransmitter? If their effect is on the calcium channels, which of the various subtypes is affected? If their action is postsynaptic, do they modulate the excitability of the postsynaptic neurones or are their effects explicable in terms of modulation of the postsynaptic receptors? If the latter, which specific receptors are involved? The first detailed studies of the action of general anaesthetics on synaptic transmission were carried out by Bremer and Bonnet10Bonnet V Bremer F Analyse oscillographique des depressions fonctionelles de la substance grise spinale.Arch Int Physiol. 1948; 56: 97-99Google Scholar 12Bremer F Bonnet V Action particuliere des barbituriques sur la transmission synaptique centrale.Arch Int Physiol. 1948; 56: 100-102Google Scholar on the frog spinal cord and by Larrabee and Posternak52Larrabee MG Posternak JM Selective actions of anesthetics on synapses and axons in mammalian sympathetic ganglia.J Neurophysiol. 1952; 15: 92-114Google Scholar in mammalian sympathetic ganglia. Both pairs of authors found that many general anaesthetics depressed excitatory synaptic transmission without significantly depressing the propagation of action potentials in nerve axons. These early studies gave rise to the idea that anaesthetics exert a selective depressant action on the process of synaptic transmission. Subsequent investigations established that a wide variety of general anaesthetics depress excitatory synaptic transmission both in the spinal cord85Somjen GG Effects of thiopental on spinal presynaptic terminals.J Pharmacol Exp Ther. 1963; 140: 396-402PubMed Google Scholar, 86Somjen GG Gill M The mechanism of blockade of synaptic transmission in the mammalian spinal cord by diethyl ether and thiopental.J Pharmacol Exp Ther. 1963; 140: 19-30PubMed Google Scholar 93Weakly JN Effect of barbiturates on ‘quantal’ synaptic transmission in spinal motoneurones.J Physiol (Lond). 1969; 204: 63-77Crossref Scopus (164) Google Scholar and in the brain.31el-Beheiry H Puil E Anaesthetic depression of excitatory synaptic transmission in neocortex.Exp Brain Res. 1989; 77: 87-93Crossref PubMed Scopus (47) Google Scholar 74Richards CD On the mechanism of barbiturate anaesthesia.J Physiol (Lond). 1972; 227: 749-767Crossref Scopus (144) Google Scholar, 75Richards CD On the mechanism of halothane anaesthesia.J Physiol (Lond). 1973; 233: 439-456Crossref Scopus (58) Google Scholar, 76Richards CD Russell WJ Smaje JC The action of ether and methoxyflurane on synaptic transmission in isolated preparations of the mammalian cortex.J Physiol (Lond). 1975; 248: 121-142Crossref Scopus (57) Google Scholar 78Richards CD Strupinski K An analysis of the action of pentobarbitone on the excitatory post-synaptic potentials and membrane properties of neurones in the guinea-pig olfactory cortex.Br J Pharmacol. 1986; 89: 321-325Crossref PubMed Scopus (10) Google Scholar, 79Richards CD White AE The actions of volatile anaesthetics on synaptic transmission in the dentate gyrus.J Physiol (Lond). 1975; 252: 241-257Crossref Scopus (103) Google Scholar Not all excitatory synapses, however, are easily blocked. Whereas those of, say, the olfactory cortex or hippocampus are readily depressed by modest concentrations of general anaesthetics, the excitatory dendrodendritic synapses of the olfactory bulb are relatively resistant to most anaesthetics.64Nicoll RA The effects of anaesthetics on synaptic excitation and inhibition in the olfactory bulb.J Physiol (Lond). 1972; 223: 803-814Crossref Scopus (177) Google Scholar Synaptic transmission through the cuneate nucleus has even been reported to be facilitated by clinically effective concentrations of general anaesthetics.63Morris ME Facilitation of synaptic transmission by general anaesthetics.J Physiol (Lond). 1978; 284: 307-325Crossref Scopus (28) Google Scholar In contrast to their predominantly depressant effect on excitation, general anaesthetics have been found to enhance inhibitory synaptic transmission both in the spinal cord27Eccles JC Schmidt RF Willis WD Pharmacological studies on presynaptic inhibition.J Physiol (Lond). 1963; 168: 500-530Crossref Scopus (544) Google Scholar and in the brain.37Gage 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, 64Nicoll RA The effects of anaesthetics on synaptic excitation and inhibition in the olfactory bulb.J Physiol (Lond). 1972; 223: 803-814Crossref Scopus (177) Google Scholar 66Nicoll RA Eccles JC Oshima T Rubia F Prolongation of hippocampal inhibitory postsynaptic potentials by barbiturates.Nature. 1975; 258: 625-627Crossref PubMed Scopus (261) Google Scholar Nevertheless, transmission at some inhibitory synapses is depressed.31el-Beheiry H Puil E Anaesthetic depression of excitatory synaptic transmission in neocortex.Exp Brain Res. 1989; 77: 87-93Crossref PubMed Scopus (47) Google Scholar, 35Fujiwara N Higashi H Nishi S Shimoji K Sugita S Yoshimura M Changes in spontaneous firing patterns of rat hippocampal neurones induced by volatile anaesthetics.J Physiol (Lond). 1988; 402: 155-175Crossref Scopus (62) Google Scholar From this it is apparent that different synapses show different degrees of susceptibility to modulation by anaesthetics. Different synapses are specialized to perform different functions. Some are concerned with reliable onward transmission of information (e.g. the synapses of the cuneate nucleus and those of primary afferents ending on spinal motor neurones), whereas others are concerned with more integrative activity in which individual synaptic contacts may be relatively weak and plastic (e.g. those of the cerebral cortex and hippocampus). It is therefore not surprising that different synapses respond in different ways to anaesthetic agents. In all cases it is necessary to determine to what extent the effect of a particular anaesthetic is presynaptic and to what extent it is postsynaptic. This can only be established by a detailed study of the effects of a variety of anaesthetics on specific synaptic systems. In what follows, the various mechanisms by which anaesthetics modulate fast excitatory and inhibitory synaptic transmission in the brain and spinal cord will be explored. Discussion of their effects on slow synaptic transmission in the CNS is limited by a paucity of experimental data. Matthews and Quilliam61Matthews EK Quilliam JP Effects of central depressant drugs on acetylcholine release.Br J Pharmacol. 1964; 22: 415-440Google Scholar provided the first direct evidence that anaesthetics could depress the amount of transmitter secreted in response to nerve impulses. They found that the amount of acetylcholine secreted in response to stimulation of preganglionic sympathetic nerves was decreased by amylobarbital and a number of other central depressants. A decrease in the amount of transmitter secreted in response to each nerve impulse could result from a number of different factors: anaesthetics could prevent action potentials fully invading the axonal arbour and thereby decrease the synaptic drive to the postsynaptic neurones.8Berg-Johnsen J Langmoen IA The effect of isoflurane on unmyelinated and myelinated fibres in the rat brain.Acta Physiol Scand. 1986; 127: 87-93Crossref PubMed Scopus (44) Google Scholar 52Larrabee MG Posternak JM Selective actions of anesthetics on synapses and axons in mammalian sympathetic ganglia.J Neurophysiol. 1952; 15: 92-114Google Scholar 92Wall PD The mechanisms of general anesthesia.Anesthesiology. 1967; 28: 46-53Crossref PubMed Scopus (37) Google Scholar This would lead to the silencing of a proportion of the normal synaptic contacts and result in decreased excitation of the postsynaptic neurones. Alternatively, as discussed above, their effects might result from direct effects on the process of exocytosis itself, either by inhibiting calcium entry into the presynaptic bouton or by direct action on the exocytotic machinery. Until recently, the small size of CNS axons and their collaterals made it difficult to determine whether general anaesthetics could affect adversely the propagation of action potentials into all the branches of an axon. To determine whether this was indeed the case required direct measurement of action potentials through identified branch-points in central axons. In the mammalian CNS this is impossible with classical electrophysiological methods. However, recent advances in confocal32Emptage N Bliss TV Fine A Single synaptic events evoke NMDA receptor-mediated release of calcium from internal stores in hippocampal dendritic spines.Neuron. 1999; 22: 115-124Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar and two-photon microscopy22Cox CL Denk W Tank DW Svoboda K Action potentials reliably invade axonal arbors of rat neocortical neurons.Proc Natl Acad Sci USA. 2000; 97: 9724-9728Crossref PubMed Scopus (112) Google Scholar, 49Koester HJ Sakmann B Calcium dynamics associated with action potentials in single nerve terminals of pyramidal cells in layer 2/3 of the young rat neocortex.J Physiol (Lond). 2000; 529: 625-646Crossref Scopus (215) Google Scholar have provided a way of following the action potential invasion of small axons and their collaterals. The method depends on the fact that the arrival of an action potential at a given point along the axon will cause voltage-gated calcium channels to open, resulting in calcium influx and an increase in intracellular free calcium concentration. Localized measurements of intracellular free calcium concentration with fluorescent calcium indicators can therefore reveal whether an action potential has invaded an axon, collateral or synaptic bouton. Using this approach, Baudoux and colleagues5Baudoux S Empson RM Richards CD Action potential propagation in the hippocampus and its modulation by general anaesthetics studies by two photon microscopy.Soc Neurosci Abstr. 2001; : 711.3Google Scholar 5aBaudoux S Empson RM Richards CD Anesthetic action on excitatory synapses.in: Urban BW Barann M Molecular and Basic Mechanisms of Anesthesia. Pabst Scientific Publishers, Berlin2002Google Scholar have shown recently that neither pentobarbital nor etomidate prevent action potentials invading the axonal arbour (Fig. 3). Perhaps more surprisingly, they also found that concentrations of procaine sufficient to reduce the amplitude of the action potential by about 20% did not prevent action potential propagation through branch-points. This strongly suggests that axonal propagation into the axonal arbour has a high safety factor and is therefore reliable. If failure of the action potential to invade the synaptic boutons is not the mechanism by which anaesthetics depress the secretion of neurotransmitter, what is responsible? Direct effects on the neurosecretory process itself have been implicated. Measurement of the effects of anaesthetics on the chemically evoked release of various neurotransmitters has shown that the secretion of neurotransmitters is depressed by a variety of anaesthetics. Thus, the potassium-evoked secretion of glutamate from slices of rat brain is inhibited by pentobarbital.21Collins GCCS Release of endogenous amino acid neuro transmitters from rat olfactory cortex: possible regulatory mechanisms and effects of pentobarbitone.Brain Res. 1980; 190: 517-523Crossref PubMed Scopus (51) Google Scholar More recent work83Schlame 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 (124) Google Scholar has shown that volatile anaesthetics also depress the secretion of glutamate by isolated synaptic boutons (synaptosomes). Some authors have reported that anaesthetic concentrations of barbiturates slightly increase the secretion of the inhibitory amino acid neurotransmitter GABA,21Collins GCCS Release of endogenous amino acid neuro transmitters from rat olfactory cortex: possible regulatory mechanisms and effects of pentobarbitone.Brain Res. 1980; 190: 517-523Crossref PubMed Scopus (51) Google Scholar which could explain why barbiturates potentiate synaptically mediated inhibition. Other workers, however, have found that GABA secretion is inhibited by anaesthetics.46Jessell TM Richards CD Barbiturate potentiation of hippocampal ipsps is not mediated by blockade of GABA uptake.J Physiol (Lond). 1977; 269: 42PGoogle Scholar, 48Kendall TJG Minchin MCW The effects of anaesthetics on the uptake and release of amino acid neurotransmitters in thalamic slices.Br J Pharmacol. 1982; 75: 219-227Crossref PubMed Scopus (35) Google Scholar 62Minchin MCW The effect of anaesthetics on the uptake and release of γ-amino butyric acid and D-aspartate in rat brain slices.Br J Pharmacol. 1981; 73: 681-690Crossref PubMed Scopus (51) Google Scholar Because the fundamental steps of neurosecretion are not thought to be different for different neurotransmitters, the balance of the evidence must favour the idea that neurosecretion is either unaffected or inhibited by anaesthetics. What is the mechanism by which anaesthetics inhibit neurosecretion? The small size of most nerve endings and the heterogeneity of brain tissue make this question difficult to answer for synapses in the brain. Instead, it has proved more useful to study the effects of anaesthetics on the secretion of epinephrine and norepinephrine from adrenal medullary chromaffin cells. These endocrine cells are, like neurones, derived from neural crest tissue and share many of the properties of sympathetic postganglionic neurones. Their neurosecretory properties have been studied intensively and correspond closely to those of nerve endings. Göthert and his colleagues,38Go¨thert M Dorn W Loewenstein I Inhibition of catecholamine release from the adrenal medulla by halothane. Site and mechanism of action.Naunyn-Schmiederbergs Arch Exp Pharmacol. 1976; 294: 239-249Crossref PubMed Scopus (24) Google Scholar, 39Go¨thert M Wendt J Inhibition of adrenal medullary catecholamine secretion by enflurane. I. Investigations in vitro.Anesthesiology. 1977; 46: 400-403PubMed Google Scholar using perfused adrenal glands, showed that anaesthetics depress the secretion of catecholamines evoked by nicotinic agonists and depolarization with high concentrations of potassium. Subse quently, Charlesworth and colleagues18Charlesworth P Pocock G Richards CD Calcium channel currents in bovine adrenal chromaffin cells and their modulation by anaesthetic agents.J Physiol (Lond). 1994; 481: 543-553Crossref Scopus (21) Google Scholar and Pocock and Richards70Pocock G Richards CD The action of pentobarbitone on stimulus–secretion coupling in adrenal chromaffin cells.Br J Pharmacol. 1987; 90: 71-80Crossref PubMed Scopus (20) Google Scholar, 71Pocock G Richards CD The action of volatile anaesthetics on stimulus–secretion coupling in bovine adrenal chromaffin cells.Br J Pharmacol. 1988; 95: 209-217Crossref PubMed Scopus (54) Google Scholar used isolated chromaffin cells to investigate the action of a wide variety of anaesthetics on neurosecretion. They found that all the general anaesthetics they investigated could inhibit catecholamine secretion evoked by direct depolarization with high concentrations of K+. For most clinically useful agents, the inhibition of secretion occurred within the range of concentrations expected during general anaesthesia. A number of mechanisms could account for this depression of secretion: anaesthetics could decrease the amount of catecholamine in each secretory granule; they could disrupt the mechanism of exocytosis itself in some way, for example by inhibiting the docking of secretory granules at the plasma membrane; or they could inhibit the entry of calcium in response to depolarization by blockade of the voltage-activated calcium channels. First, do anaesthetics decrease the catecholamine content of chromaffin granules or the transmitter content of synaptic vesicles? A thorough study by Akeson and Deamer2Akeson MA Deamer DW Steady-state catecholamine distribution in chromaffin granules.Biochemistry. 1989; 28: 5120-5127Crossref PubMed Scopus (12) Google Scholar showed that anaesthetics did not deplete isolated chromaffin granules of their catecholamines. Furthermore, Pocock and Richards72Pocock G Richards CD Anesthetic action on stimulus-secretion coupling.Ann NY Acad Sci. 1991; 625: 71-81Crossref PubMed Scopus (4) Google Scholar found that a variety of anaesthetics were without effect on the leakage of catecholamines from isolated chromaffin cells rendered leaky to small molecules by exposure to high-voltage electrical discharge (electropermeabilized cells) (Fig. 4). Equally, the content of neurotransmitter in brain tissue does not decline in anaesthesia. It is either unchanged or is increased depending on the transmitter studied.73Pocock G Richards CD Excitatory and inhibitory synaptic mechanisms in anaesthesia.Br J Anaesth. 1993; 71: 134-147Crossref PubMed Scopus (110) Google Scholar Secondly, do anaesthetics inhibit the intracellular events that lead to exocytosis? To investigate this possibility Pocock and Richards72Pocock G Richards CD Anesthetic action on stimulus-secretion coupling.Ann NY Acad Sci. 1991; 625: 71-81Crossref PubMed Scopus (4) Google Scholar examined the effects of three types" @default.
W2077993124 created "2016-06-24" @default.
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W2077993124 date "2002-07-01" @default.
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W2077993124 title "Anaesthetic modulation of synaptic transmission in the mammalian CNS" @default.
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