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MACHANISMS OF GENERAL ANAESTHESIA
"I would have everie man write what he knowes and no more."—MONTAIGNE
BRITISH JOURNAL OF ANAESTHESIA VOLUME 55, No. 3
MARCH 1983
EDITORIAL
General anaesthesia can be produced by a variety of chemicals with greatly differing structures. It is characterized by three states: a loss of reaction to painful stimuli, a loss of awareness of immediate events and a loss of memory for those events. Exactly how these states are produced has long been a source of speculation. Approaches to solving the problem can be divided into two main classes—one looking at the properties of the anaesthetics and the second looking at the neurophysiological effects produced by them. The physical properties of the anaesthetics are the most relevant in that it seems likely that the formation of chemical bonds between anaesthetics and some specific receptors in the brain is not a feature of most anaesthetics. The well-known correlation between anaesthetic potency and solubility in olive oil (Meyer, 1901; Overton, 1901) indicates a probable interaction between the anaesthetic and a hydrophobic area of the brain. Further developments have looked at anaesthetic thermodynamic potentials (Ferguson, 1939) and the expansion of lipid membranes by a critical volume of dissolved anaesthetic (Mullins, 1954). These theories and the fascinating evidence of reversal of anaesthesia by high ambient pressures have been reviewed by Wardley-Smith and Halsey (1979). The Northwick Park group have also produced evidence to show that it is unlikely that a single site in the brain is the target of "anaesthesia" (Halsey, Wardley-Smith and Green, 1979). They propose that more than one site is involved and that the interaction with pressure suggests that solubility or volume expansion are not the sole factors. It will be interesting to see how this multi-site theory develops. The second approach uses techniques associated
with neurophysiology to look at overall brain function and at its components. The three papers presented in this issue look at the problems of consciousness and at synaptic transmission. The evidence available suggests that synaptic transmission is the process likely to be most vulnerable to anaesthetics. Brain metabolism is reduced by anaesthesia, but this seems to follow the reduction in electrical activity rather than precede it. What is becoming exciting is the union of physiochemical and physiological approaches. Studies on synaptic transmission in invertebrates show individual cells in the nervous system which are constant from animal to animal and whose excitatory and inhibitory transmitters are known. Further, the biophysical events associated with the transmitterinduced changes are identifiable. Channels in the surface membrane open to allow passage of selected ions. Some channels can be opened by electrical depolarization, whilst some can be opened by transmitters. Anaesthetics may be acting by blocking the effect of transmitter on the receptor or by blocking the subsequent conformational change in the channel. These events are occurring in the surface membrane of the neuron—which is the site where the anaesthetic is likely to present. It is a hydrophobic area. Judge (1983) reviews this area of work and Richards (1983) extends it into studies in mammalian systems. We still need to explore how much anaesthetics affect all synapses, whether block of excitation is the important factor, whether changes in inhibitory transmission are important, and finally whether specific synapses in parts of the brain need to be affected to produce the states of anaesthesia. The reticular activating system has been considered a
Downloaded from http://bja.oxfordjournals.org/ at Carleton University on June 23, 2015
MECHANISMS OF GENERAL ANAESTHESIA
BRITISH JOURNAL OF ANAESTHESIA
190
prime target area (see Richards, 1980 for a review) and Angel (1979) has reviewed the actions of anaesthetics on the sensory and motor systems of the brain. Finally, we still need to determine whether the knowledge of the mechanisms of anaesthetic action on the brain will allow us to define the properties we need in future anaesthetic drugs. /. Norman REFERENCES
Chem.Rev., 54,289. Overton, E. (1901). Studien uber die Narkou. Jena: Fisher. Richards, C. D. (1980). The mechanisms of general anaesthesia; in Topical Reviews in Anaesthesia, Vol. 1 (eds J. Norman and J. G. Whitwam), p. 1. Bristol: John Wright & Sons Ltd. (1983). Actions of general anaesthetics on synaptic transmission in the CNS. Br. J. Anaesth., 55,201. Wardley-Smith, B., and Halsey, M. J. (1979). Recent molecular theories of general anaesthesia. Br. J. Anaesth., 51,619.
Downloaded from http://bja.oxfordjournals.org/ at Carleton University on June 23, 2015
Angel, A. (1979). Effect of anaesthetics on nervous pathways; in General Anaesthesia, 4th edn, Vol. 1 (eds T. C. Gray, J. F. Nunn and J. Utting), p. 117. London: Butterworths. Ferguson, J. (1939). The use of chemical potentials as indices of toxkity. Proc. R. Soc. B., 127, 387.
Halsey, M. J., Wardley-Smith, B., and Green, C. J. (1979). Pressure-reversal of general anaesthesia—a multi-site expansion hypothesis. Br. J. Anaesth., 50,1091. Judge, S. E. (1983). Effect of general anaesthetics on synoptic ion channels. Br. J. Anaesth., 55,191. Meyer, H. H. (1901). Zur Theorie der Alkoholnarkose. Arch. Exp. Pathol. Pharmacol., 46, 338. MuUins, L. J. (1954). Some physical mechanisms in narcosis.
BRITISH JOURNAL OF ANAESTHESIA VOLUME 55, No. 3
MARCH 1983
EDITORIAL
General anaesthesia can be produced by a variety of chemicals with greatly differing structures. It is characterized by three states: a loss of reaction to painful stimuli, a loss of awareness of immediate events and a loss of memory for those events. Exactly how these states are produced has long been a source of speculation. Approaches to solving the problem can be divided into two main classes—one looking at the properties of the anaesthetics and the second looking at the neurophysiological effects produced by them. The physical properties of the anaesthetics are the most relevant in that it seems likely that the formation of chemical bonds between anaesthetics and some specific receptors in the brain is not a feature of most anaesthetics. The well-known correlation between anaesthetic potency and solubility in olive oil (Meyer, 1901; Overton, 1901) indicates a probable interaction between the anaesthetic and a hydrophobic area of the brain. Further developments have looked at anaesthetic thermodynamic potentials (Ferguson, 1939) and the expansion of lipid membranes by a critical volume of dissolved anaesthetic (Mullins, 1954). These theories and the fascinating evidence of reversal of anaesthesia by high ambient pressures have been reviewed by Wardley-Smith and Halsey (1979). The Northwick Park group have also produced evidence to show that it is unlikely that a single site in the brain is the target of "anaesthesia" (Halsey, Wardley-Smith and Green, 1979). They propose that more than one site is involved and that the interaction with pressure suggests that solubility or volume expansion are not the sole factors. It will be interesting to see how this multi-site theory develops. The second approach uses techniques associated
with neurophysiology to look at overall brain function and at its components. The three papers presented in this issue look at the problems of consciousness and at synaptic transmission. The evidence available suggests that synaptic transmission is the process likely to be most vulnerable to anaesthetics. Brain metabolism is reduced by anaesthesia, but this seems to follow the reduction in electrical activity rather than precede it. What is becoming exciting is the union of physiochemical and physiological approaches. Studies on synaptic transmission in invertebrates show individual cells in the nervous system which are constant from animal to animal and whose excitatory and inhibitory transmitters are known. Further, the biophysical events associated with the transmitterinduced changes are identifiable. Channels in the surface membrane open to allow passage of selected ions. Some channels can be opened by electrical depolarization, whilst some can be opened by transmitters. Anaesthetics may be acting by blocking the effect of transmitter on the receptor or by blocking the subsequent conformational change in the channel. These events are occurring in the surface membrane of the neuron—which is the site where the anaesthetic is likely to present. It is a hydrophobic area. Judge (1983) reviews this area of work and Richards (1983) extends it into studies in mammalian systems. We still need to explore how much anaesthetics affect all synapses, whether block of excitation is the important factor, whether changes in inhibitory transmission are important, and finally whether specific synapses in parts of the brain need to be affected to produce the states of anaesthesia. The reticular activating system has been considered a
Downloaded from http://bja.oxfordjournals.org/ at Carleton University on June 23, 2015
MECHANISMS OF GENERAL ANAESTHESIA
BRITISH JOURNAL OF ANAESTHESIA
190
prime target area (see Richards, 1980 for a review) and Angel (1979) has reviewed the actions of anaesthetics on the sensory and motor systems of the brain. Finally, we still need to determine whether the knowledge of the mechanisms of anaesthetic action on the brain will allow us to define the properties we need in future anaesthetic drugs. /. Norman REFERENCES
Chem.Rev., 54,289. Overton, E. (1901). Studien uber die Narkou. Jena: Fisher. Richards, C. D. (1980). The mechanisms of general anaesthesia; in Topical Reviews in Anaesthesia, Vol. 1 (eds J. Norman and J. G. Whitwam), p. 1. Bristol: John Wright & Sons Ltd. (1983). Actions of general anaesthetics on synaptic transmission in the CNS. Br. J. Anaesth., 55,201. Wardley-Smith, B., and Halsey, M. J. (1979). Recent molecular theories of general anaesthesia. Br. J. Anaesth., 51,619.
Downloaded from http://bja.oxfordjournals.org/ at Carleton University on June 23, 2015
Angel, A. (1979). Effect of anaesthetics on nervous pathways; in General Anaesthesia, 4th edn, Vol. 1 (eds T. C. Gray, J. F. Nunn and J. Utting), p. 117. London: Butterworths. Ferguson, J. (1939). The use of chemical potentials as indices of toxkity. Proc. R. Soc. B., 127, 387.
Halsey, M. J., Wardley-Smith, B., and Green, C. J. (1979). Pressure-reversal of general anaesthesia—a multi-site expansion hypothesis. Br. J. Anaesth., 50,1091. Judge, S. E. (1983). Effect of general anaesthetics on synoptic ion channels. Br. J. Anaesth., 55,191. Meyer, H. H. (1901). Zur Theorie der Alkoholnarkose. Arch. Exp. Pathol. Pharmacol., 46, 338. MuUins, L. J. (1954). Some physical mechanisms in narcosis.