Dear Etienne Pralong,
I am not sure that it is possible to attribute a pharmacological basis for
the anaesthetic action of urethane or, indeed, any other general
anaesthetic agent at this time.
Early experiments by Meyer (1899) and Overton (1901) showed a high degree
of correlation between an agent's lipid solubility and its anaesthetic
potency, suggesting that perturbation of the phospholipid membrane is
important in anaesthetic action Subsequent experiments have suggested the
pressure-reversibility of general anaesthesia (for example Lever et al.,
1971; Halsey & Wardley-Smith, 1975). More recent experiments by Franks &
Lieb (1988, 1994) have suggested that anaesthetic may act primarily by
altering the behaviour of ion channels within the cell membrane.
Work in our department has concentrated on the effects of general
anaesthetics on the behaviour of one of the afferent pathways, the dorsal
column medial lemniscal pathway, in vivo. Results from these studies
(see, for example, Angel 1991) have suggested that anaesthetics may have
either the thalamic relay nucleus (in our experiments ventroposterolateral
thalamus) or primary somatosensory cortex as their site of action in
modulating the afferent transmission of somatosensory information and in
modulating cortical arousal. There is also the suggestion that the
thalamic reticular nucleus or spontaneously active cortical cells may also
have a role in modulating afferent transmission and may thus be an
important locus for anaesthetic action since they show
anaesthetic-dependant changes in discharge behaviour.
Very recent work (Angel & Arnott, 1994; Arnott & Angel, 1996) looking at
the effects of the anaesthetic agent Etomidate has suggested that the site
in the dorsal column pathway which appears to be altered by both agents
such as urethane, halothane, ether etc. and Etomidate is the cortex, rather
than the thalamus. We suggest that it may be that it is this common site
of action which is important in determining the efficacy of anaesthetics in
modulating afferent transmission.
Of course one must ask various, as yet unanswered questions. Maybe,
amongst others, one could consider the following:
If general anaesthetics exert their effects by altering the behaviour of
ion channels, how do they do this? What components of primary
somatosensory cortex are altered in their behaviour by general
anaesthetics? What is the normal physiological function of these
structures, so how might changes in their behaviour be important? Do
anaeshetics simply alter levels of cortical arousal (and, if so, how?) or
do they have a more specific, site-dependent action? Why is it that the
short-latency responsiveness of a particular group of cells (eg thalamic
VPL cells) may be altered by some anaesthetics but not by others, and yet
the cells to which VPL projects (lamina IV and VI CoSI cells) appear to be
affected by all agents?
I would recommend that you read Angel's (1991) review which covers a lot of
the work in the field. Please let me know if I can be of further help.
Best wishes,
Robert Arnott
References
Angel, A. (1991): The G.L. Brown Lecture - Adventures in Anaesthesia.
Experimental Physiology 76 1-38
Angel, A., Arnott, R.H., (1994): The effects of etomidate on sensory
transmission in the urethane-anaesthetised rat. Journal of Physiology
481.P 68P
Arnott, R. H., Angel, A. (1996): The effects of Etomidate on the mass
response of cells of cortical lamina V evoked by antidromic activation in
the urethane-anaestetised rat. British Journal of Anaesthesia. In press.
Franks, M.P., Lieb, W.R. (1988): Volatile general anaesthetics activate a
novel neuronal K+ current. Nature 333 662-664
Franks, N. P., Lieb, W.R., (1994): Molecular and cellular mechanisms of
general anaesthesia. Nature 367 (6464) 607-614
Halsey, M.J., Wardley-Smith, B. (1975): Pressure reversal of narcosis
produced by anaesthetics, narcotics and tranquilizers. Nature 258 811-813
Lever, M.J., Miler, K.W., Paton, W.D.M., Smith, E.B. (1971): Pressure
reversal of anaesthesia. Nature 231 368-371
Meyer, H. (1899): Welche Eigenschaft der Anasthetica bedingt ihre
narkitische Wirkung? Naunyn-Schmiedeberg's Archiv fuer Experimentalle
Pathologie und Pharmakologie 42 109-118
Overton, E. (1901): _Studien ueber die Narkose zugleich ein Beitrag zur
allgemeinen Pharmakologie_ Gustav Fischer, Jena.
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Robert Arnott,
Centre for Research in Anaesthetic Mechanisms,
Department of Biomedical Science,
The University of Sheffield,
SHEFFIELD.
S10 2TN
England
email r.h.arnott at sheffield.ac.uk
Telephone +44114 276 8555 ext. 4660
Fax +44114 276 5413
URL http://www.shef.ac.uk/uni/academic/A-C/amrc/
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