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Molecular mechanisms of general anaesthesia

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Abstract

Important constraints on possible molecular mechanisms of general anaesthesia are derived from a quantitative reappraisal of data on the potency of general anaesthetics on whole animals. Despite their popularity, theories that invoke lipids as the prime target do not look at all promising, and available data point much more plausibly to a direct effect on particularly sensitive proteins. Structural changes of proteins on binding general anaesthetics are probably small but may be sufficient to perturb normal function; alternatively, anaesthetics may compete with an endogenous ligand. The phenomenon of pressure reversal of anaesthesia may simply be due to anaesthetics being squeezed away from their target sites.

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References

  1. Richards, C. D. in Topical Reviews in Anaesthesia Vol. 1 (eds Norman, J. & Whitwam, J. G.) Vol. 1, 1–84 (Wright, Bristol, 1980).

    Google Scholar 

  2. Macdonald, A. G. & Wann, K. T. Physiological Aspects of Anaesthetics and Inert Gases (Academic, London, 1978).

    Google Scholar 

  3. Gray, T. C., Nunn, J. F. & Utting, J. E. General Anaesthesia Vol. 1, 4th edn (Butterworths, London, 1980).

    Google Scholar 

  4. Meyer, H. Arch. exp. Path. Pharmak. (Naunyn-Schmiedebergs) 42, 109–118 (1899).

    Google Scholar 

  5. Meyer, H. Arch. exp. Path. Pharmak. (Naunyn-Schmiedebergs) 46, 338–346 (1901).

    Google Scholar 

  6. Overton, E. Studien über die Narkose (Fischer, Jena, 1901).

    Google Scholar 

  7. Franks, N. P. & Lieb, W. R. Nature 274, 339–342 (1978).

    ADS  CAS  PubMed  Google Scholar 

  8. Miller, K. W. & Smith, E. B. in A Guide to Molecular Pharmacology-Toxicology Vol. 1 (ed. Featherstone, R. M.) 427–475 (Dekker, New York, 1973).

    Google Scholar 

  9. Steward, A., Allott, P. R., Cowles, A. L. & Mapleson, W. W. Br. J. Anaesth. 45, 282–293 (1973).

    CAS  PubMed  Google Scholar 

  10. Sandorfy, C. Anesthesiology 48, 357–359 (1978).

    CAS  PubMed  Google Scholar 

  11. Mullins, L. J. Chem. Rev. 54, 289–323 (1954).

    CAS  Google Scholar 

  12. Cherkin, A. & Catchpool, J. F. Science 144, 1460–1462 (1964).

    ADS  CAS  PubMed  Google Scholar 

  13. Mullins, L. J. in A Guide to Molecular Pharmacology-Toxicology Vol. 1 (ed. Featherstone, R. M.) 1–52 (Dekker, New York, 1973).

    Google Scholar 

  14. Hansch, C., Vittoria, A., Silipo, C. & Jow, P. Y. C. J. med. Chem. 18, 546–548 (1975).

    CAS  PubMed  Google Scholar 

  15. Katz, Y. & Simon, S. A. Biochim. biophys. Acta 471, 1–15 (1977).

    CAS  PubMed  Google Scholar 

  16. Miller, K. W., Paton, W. D. M., Smith, E. B. & Smith, R. A. Anesthesiology 36, 339–351 (1972).

    CAS  PubMed  Google Scholar 

  17. Mullins, L. J. in Alterations of Chemical Equilibrium in the Nervous System (ed. Lajtha, A.) 395–421 (Plenum, New York, 1971).

    Google Scholar 

  18. Pringle, M. J., Brown, K. B. & Miller, K. W. Molec. Pharmac. 19, 49–55 (1981).

    CAS  Google Scholar 

  19. Lever, M. J., Miller, K. W., Paton, W. D. M. & Smith, E. B. Nature 231, 368–371 (1971).

    ADS  CAS  PubMed  Google Scholar 

  20. Halsey, M. J. & Wardley-Smith, B. Nature 257, 811–813 (1975).

    ADS  CAS  PubMed  Google Scholar 

  21. Miller, K. W., Paton, W. D. M., Smith, R. A. & Smith, E. B. Molec. Pharmac. 9, 131–143 (1973).

    CAS  Google Scholar 

  22. Miller, K. W., Wilson, M. W. & Smith, R. A. Molec. Pharmac. 14, 950–959 (1978).

    CAS  Google Scholar 

  23. Moore, W. J. Physical Chemistry 4th edn (Longmans, London, 1963).

    Google Scholar 

  24. Eyring, H., Woodbury, J. W. & D'Arrigo, J. S. Anesthesiology 38, 415–424 (1973).

    CAS  PubMed  Google Scholar 

  25. Miller, K. W. & Wilson, M. W. Anesthesiology 48, 104–110 (1978).

    CAS  PubMed  Google Scholar 

  26. Halsey, M. J., Wardley-Smith, B. & Green, C. J. Br. J. Anaesth. 50, 1091–1096 (1978).

    CAS  PubMed  Google Scholar 

  27. Wardley-Smith, B. & Halsey, M. J. Br. J. Anaesth. 48, 265 (1976).

    CAS  PubMed  Google Scholar 

  28. Kendig, J. J., Schneider, T. M. & Cohen, E. N. J. appl. Physiol. 45, 742–746 (1978).

    CAS  PubMed  Google Scholar 

  29. Kendig, J. J., Schneider, T. M. & Cohen, E. N. J. appl. Physiol. 45, 747–750 (1978).

    CAS  PubMed  Google Scholar 

  30. Meyer, K. H. & Hemmi, H. Biochem. Z. 277, 39–71 (1935).

    CAS  Google Scholar 

  31. Allott, P. R., Steward, A., Flook, V. & Mapleson, W. W. Br. J. Anaesth. 45, 294–300 (1973).

    CAS  PubMed  Google Scholar 

  32. Regan, M. J. & Eger, E. I. Anesthesiology 28, 689–700 (1967).

    CAS  PubMed  Google Scholar 

  33. Eger, E. I., Saidman, L. J. & Brandstater, B. Anesthesiology 26, 764–770 (1965).

    CAS  PubMed  Google Scholar 

  34. Steffey, E. P. & Eger, E. I. Anesthesiology 41, 392–396 (1974).

    CAS  PubMed  Google Scholar 

  35. Janoff, A. S., Pringle, M. J. & Miller, K. W. Biochim. biophys. Acta 649, 125–128 (1981).

    CAS  PubMed  Google Scholar 

  36. Diamond, J. M. & Katz, Y. J. Membrane Biol. 17, 121–154 (1974).

    CAS  Google Scholar 

  37. Metcalfe, J. C., Seeman, P. & Burgen, A. S. V. Molec. Pharmac. 4, 87–95 (1968).

    CAS  Google Scholar 

  38. Franks, N. P. & Lieb, W. R. J. molec. Biol. 133, 469–500 (1979).

    CAS  PubMed  Google Scholar 

  39. Boggs, J. M., Yoong, T. & Hsia, J. C. Molec. Pharmac. 12, 127–135 (1976).

    CAS  Google Scholar 

  40. Turner, G. L. & Oldfield, E. Nature 277, 669–670 (1979).

    ADS  CAS  PubMed  Google Scholar 

  41. Lieb, W. R., Kovalycsik, M. & Mendelsohn, R. Biochim. biophys. Acta 688, 388–398 (1982).

    CAS  PubMed  Google Scholar 

  42. Rosenberg, P. H., Eibl, H. & Stier, A. Molec. Pharmac. 11, 879–882 (1975).

    CAS  Google Scholar 

  43. Pellkofer, R. & Sandhoff, K. J. Neurochem. 34, 988–992 (1980).

    CAS  PubMed  Google Scholar 

  44. Mastrangelo, C. J., Trudell, J. R., Edmunds, H. N. & Cohen, E. N. Molec. Pharmac. 14, 463–467 (1978).

    CAS  Google Scholar 

  45. Miller, K. W. & Pang, K. Y. Nature 263, 253–255 (1976).

    ADS  CAS  PubMed  Google Scholar 

  46. Richards, C. D. et al. Nature 276, 775–779 (1978).

    ADS  CAS  PubMed  Google Scholar 

  47. Neal, M. J., Butler, K. W., Polnaszek, C. F. & Smith, I. C. P. Molec. Pharmac. 12, 144–155 (1976).

    CAS  Google Scholar 

  48. Pang, K. Y., Braswell, L. M., Chang, L., Sommer, T. J. & Miller, K. W. Molec. Pharmac. 18, 84–90 (1980).

    CAS  Google Scholar 

  49. Finch, E. D. & Kiesow, L. A. Undersea biomed. Res. 6, 41–45 (1979).

    CAS  PubMed  Google Scholar 

  50. Mastrangelo, C. J., Kendig, J. J., Trudell, J. R. & Cohen, E. N. Undersea biomed. Res. 6, 47–53 (1979).

    CAS  PubMed  Google Scholar 

  51. Hill, M. W. Biochim. biophys. Acta 356, 117–124 (1974).

    CAS  PubMed  Google Scholar 

  52. Mountcastle, D. B., Biltonen, R. L. & Halsey, M. J. Proc. natn. Acad. Sci. U.S.A. 75, 4906–4910 (1978).

    ADS  CAS  Google Scholar 

  53. Kamaya, H., Ueda, I., Moore, P. S. & Eyring, H. Biochim. biophys. Acta 550, 131–137 (1979).

    CAS  PubMed  Google Scholar 

  54. Lee, A. G. Biochemistry 15, 2448–2454 (1976).

    CAS  PubMed  Google Scholar 

  55. Pringle, M. J. & Miller, K. W. Biochemistry 15, 3314–3320 (1979).

    Google Scholar 

  56. Trudell, J. R. Anesthesiology 46, 5–10 (1977).

    CAS  PubMed  Google Scholar 

  57. Skou, J. C. Biochim. biophys. Acta 30, 625–629 (1958).

    CAS  PubMed  Google Scholar 

  58. Clements, J. A. & Wilson, K. M. Proc. natn. Acad. Sci. U.S.A. 48, 1008–1014 (1962).

    ADS  CAS  Google Scholar 

  59. Bangham, A. D., Standish, M. M. & Miller, N. Nature 208, 1295–1297 (1965).

    ADS  CAS  PubMed  Google Scholar 

  60. Ueda, I., Shieh, D. D. & Eyring, H. Anesthesiology 41, 217–225 (1974).

    CAS  PubMed  Google Scholar 

  61. Seeman, P. & Roth, S. Biochim. biophys. Acta 255, 171–177 (1972).

    CAS  PubMed  Google Scholar 

  62. Haydon, D. A., Hendry, B. M., Levinson, S. R. & Requena, J. Nature 268, 356–358 (1977).

    ADS  CAS  PubMed  Google Scholar 

  63. Haydon, D. A., Requena, J. & Urban, B. W. J. Physiol., Lond. 309, 229–245 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. McIntosh, T. J., Simon, S. A. & MacDonald, R. C. Biochim. biophys. Acta 597, 445–463 (1980).

    CAS  PubMed  Google Scholar 

  65. Ashcroft, R. G., Coster, H. G. L. & Smith, J. R. Nature 269, 819–820 (1977).

    ADS  CAS  PubMed  Google Scholar 

  66. Ebihara, L., Hall, J. E., MacDonald, R. C., McIntosh, T. J. & Simon, S. A. Biophys. J. 28, 185–196 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Elliott, J. R. & Haydon, D. A. Biochim. biophys. Acta 557, 259–263 (1979).

    CAS  PubMed  Google Scholar 

  68. Reyes, J. & Latorre, R. Biophys. J. 28, 259–279 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Padron, R., Mateu, L. & Requena, J. Biochim. biophys. Acta 602, 221–233 (1980).

    CAS  PubMed  Google Scholar 

  70. Seeman, P. Pharmac. Rev. 24, 583–655 (1972).

    CAS  Google Scholar 

  71. Seeman, P. Experientia 30, 759–760 (1974).

    CAS  PubMed  Google Scholar 

  72. Franks, N. P. & Lieb, W. R. Nature 292, 248–251 (1981).

    ADS  CAS  PubMed  Google Scholar 

  73. Kita, Y., Bennett, L. J. & Miller, K. W. Biochim. biophys. Acta 647, 130–139 (1981).

    CAS  PubMed  Google Scholar 

  74. Trudell, J. R. Biochim. biophys. Acta 470, 509–510 (1977).

    CAS  PubMed  Google Scholar 

  75. Seeman, P. Biochim. biophys. Acta 183, 520–529 (1969).

    CAS  PubMed  Google Scholar 

  76. Rand, R. P. & Pangborn, W. A. Biochim. biophys: Acta 318, 299–305 (1973).

    CAS  Google Scholar 

  77. Melchior, D. L., Scavitto, F. J. & Steim, J. M. Biochemistry 19, 4828–4834 (1980).

    CAS  PubMed  Google Scholar 

  78. Johnson, S. M. & Bangham, A. D. Biochim. biophys. Acta 193, 92–104 (1969).

    CAS  PubMed  Google Scholar 

  79. Johnson, S. M., Miller, K. W. & Bangham, A. D. Biochim. biophys. Acta 307, 42–57 (1973).

    CAS  PubMed  Google Scholar 

  80. Pang, K., Chang, T. & Miller, K. W. Molec. Pharmac. 15, 729–738 (1979).

    CAS  Google Scholar 

  81. Nichols, J. W. & Deamer, D. W. Proc. natn. Acad. Sci. U.S.A. 77, 2038–2042 (1980).

    ADS  CAS  Google Scholar 

  82. Bangham, A. D. & Mason, W. T. Anesthesiology 53, 135–141 (1980).

    CAS  PubMed  Google Scholar 

  83. Toll, L. & Howard, B. D. Biochemistry 17, 2517–2523 (1978).

    CAS  PubMed  Google Scholar 

  84. Gutknecht, J. & Walter, A. Biochim. biophys. Acta 641, 183–188 (1981).

    CAS  PubMed  Google Scholar 

  85. Nozaki, Y. & Tanford, C. Proc. natn. Acad. Sci. U.S.A. 78, 4324–4328 (1981).

    ADS  CAS  Google Scholar 

  86. Wishnia, A. & Pinder, T. Biochemistry 3, 1377–1384 (1964).

    CAS  PubMed  Google Scholar 

  87. Ray, A., Reynolds, J. A., Polet, H. & Steinhardt, J. Biochemistry 5, 2606–2616 (1966).

    CAS  PubMed  Google Scholar 

  88. Helmer, F., Kiehs, K. & Hansch, C. Biochemistry 7, 2858–2863 (1968).

    CAS  PubMed  Google Scholar 

  89. Kiehs, K., Hansch, C. & Moore, L. Biochemistry 5, 2602–2605 (1966).

    CAS  PubMed  Google Scholar 

  90. Weber, G. & Young, L. B. J. biol. Chem. 239, 1415–1423 (1964).

    CAS  PubMed  Google Scholar 

  91. Wishnia, A. Biochemistry 8, 5064–5070 (1969).

    CAS  PubMed  Google Scholar 

  92. Schoenborn, B. P. Nature 208, 760–762 (1965).

    ADS  CAS  PubMed  Google Scholar 

  93. Wishnia, A. & Pinder, T. W. Biochemistry 5, 1534–1542 (1966).

    CAS  PubMed  Google Scholar 

  94. Sachsenheimer, W., Pai, E. F., Schultz, G. & Schirmer, R. H. FEBS Lett. 79, 310–312 (1977).

    CAS  PubMed  Google Scholar 

  95. Brown, F. F., Halsey, M. J. & Richards, R. E. Proc. R. Soc. B193, 387–411 (1976).

    ADS  CAS  Google Scholar 

  96. Millar, R. A., Beard, D. J. & Hulands, G. H. Br. J. Anaesth. 43, 1003–1011 (1971).

    CAS  PubMed  Google Scholar 

  97. Miller, J. C. & Miller, K. W. in Physiological and Pharmacological Biochemistry (ed. Blaschko, H. K. F.) 33–76 (Butterworths, London, 1975).

    Google Scholar 

  98. Hulands, G. H., Beard, D. J. & Brammell, A. in Molecular Mechanisms in Anesthesia Vol. 1 (ed. Fink, B. R.) 501–507 (Raven, New York, 1975).

    Google Scholar 

  99. Levitt, J. D. Anesthesiology 42, 267–274 (1975).

    CAS  PubMed  Google Scholar 

  100. Fairhurst, A. S. & Liston, P. Eur. J. Pharmac. 58, 59–66 (1979).

    CAS  Google Scholar 

  101. LaBella, F. S., Pinsky, C., Havlicek, V. & Queen, G. in Endogenous and Exogenous Opiate Agonists and Antagonists (ed. Way, E. L.) 71–74 (Pergamon, New York, 1980).

    Google Scholar 

  102. Baker, P. F. & Schapira, A. H. V. Nature 284, 168–169 (1980).

    ADS  CAS  PubMed  Google Scholar 

  103. Johnson, F. H., Eyring, H. & Polissar, M. J. The Kinetic Basis of Molecular Biology (Wiley, New York, 1954).

    Google Scholar 

  104. White, D. C. & Dundas, C. R. Nature 226, 456–458 (1970).

    ADS  CAS  PubMed  Google Scholar 

  105. Halsey, M. J. & Smith, E. B. Nature 227, 1363–1365 (1970).

    ADS  CAS  PubMed  Google Scholar 

  106. Middleton, A. J. & Smith, E. B. Proc. R. Soc. B193, 173–190 (1976).

    ADS  CAS  Google Scholar 

  107. Ueda, I. & Kamaya, H. Anesthesiology 38, 425–436 (1973).

    CAS  PubMed  Google Scholar 

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Franks, N., Lieb, W. Molecular mechanisms of general anaesthesia. Nature 300, 487–493 (1982). https://doi.org/10.1038/300487a0

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