Skip to main content
PMC home page
The Journal of General Physiology logoLink to The Journal of General Physiology
. 1964 Nov 1;48(2):357–374. doi: 10.1085/jgp.48.2.357

Reaction of Local Anesthetics with Phospholipids

A possible chemical basis for anesthesia

Maurice B Feinstein 1
PMCID: PMC2195417  PMID: 14225262

Abstract

Local anesthetics (LA) have been found to interact with phospholipids and lipids extracted from nerve and muscle. This reaction is demonstrated by: (a) Inhibition by LA of phospholipid (and tissue lipid) facilitated transport of calcium from a methanol: water phase into chloroform. This action is dependent upon the cationic form of the LA. (b) LA increase the electrical resistance of "membranes" prepared by impregnating Millipore filters with cephalin:cholesterol or tissue lipid extracts and bathed with NaCl or KCl solutions. (c) LA coagulate aqueous dispersions of cephalin, phosphatidyl serine, phosphatidyl ethanolamine, and inositide, an action shared by calcium. The order of potency in coagulating cephalin sols is tetracaine > calcium > butacaine > procaine. Na+ and K+ do not coagulate phospholipid dispersions at 0.1 M concentration and antagonize the effect of Ca2+. (d) LA produce a marked fall in the pH of cephalin sols equivalent to that produced by calcium, (e) Ca2+ and LA form 1:2 molar complexes with phospholipids probably by ion-ion and ion-induced polar type of binding at the phosphate groups of the lipid. It is suggested that such reactions with cell membrane phospholipids may underlie inhibitory effects of LA on cellular ion fluxes and provide a chemical basis for anesthetic action.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ABRAMSON M. B., KATZMAN R., GREGOR H. P. AQUEOUS DISPERSIONS OF PHOSPHATIDYLSERINE. IONIC PROPERTIES. J Biol Chem. 1964 Jan;239:70–76. [PubMed] [Google Scholar]
  2. ACEVES J., MACHNE X. The action of calcium and of local anesthetics on nerve cells, and their interaction during excitation. J Pharmacol Exp Ther. 1963 May;140:138–148. [PubMed] [Google Scholar]
  3. CONDOURIS G. A. A study on the mechanism of action of cocaine on amphibian peripheral nerve. J Pharmacol Exp Ther. 1961 Feb;131:243–249. [PubMed] [Google Scholar]
  4. CONDOURIS G. A. CONDUCTION BLOCK BY COCAINE IN SODIUM-DEPLETED NERVES WITH ACTIVITY MAINTAINED BY LITHIUM, HYDRAZINIUM OR GUANIDINIUM IONS. J Pharmacol Exp Ther. 1963 Aug;141:253–259. [PubMed] [Google Scholar]
  5. DAVIS F. A., DETTBARN W. D. Depolarizing action of calciumion depletion on frog nerve and its inhibition by compounds acting on the acetylcholine system. Biochim Biophys Acta. 1962 Oct 8;63:349–357. doi: 10.1016/0006-3002(62)90098-7. [DOI] [PubMed] [Google Scholar]
  6. DETTBARN W. D. The active form of local anesthetics. Biochim Biophys Acta. 1962 Feb 12;57:73–76. doi: 10.1016/0006-3002(62)91079-x. [DOI] [PubMed] [Google Scholar]
  7. EHRENPREIS S. ACETYLCHOLINE AND NERVE ACTIVITY. Nature. 1964 Feb 29;201:887–893. doi: 10.1038/201887a0. [DOI] [PubMed] [Google Scholar]
  8. EHRENPREIS S. Isolation and identification of the acetylcholine receptor protein of electric tissue. Biochim Biophys Acta. 1960 Nov 18;44:561–577. doi: 10.1016/0006-3002(60)91610-3. [DOI] [PubMed] [Google Scholar]
  9. FEINSTEIN M. B. INHIBITION OF CAFFEINE RIGOR AND RADIOCALCIUM MOVEMENTS BY LOCAL ANESTHETICS IN FROG SARTORIUS MUSCLE. J Gen Physiol. 1963 Sep;47:151–172. doi: 10.1085/jgp.47.1.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. FRANKENHAEUSER B. The effect of calcium on the myelinated nerve fibre. J Physiol. 1957 Jul 11;137(2):245–260. doi: 10.1113/jphysiol.1957.sp005809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. FRANK G. B., SANDERS H. D. A PROPOSED COMMON MECHANISM OF ACTION FOR GENERAL AND LOCAL ANAESTHETICS IN THE CENTRAL NERVOUS SYSTEM. Br J Pharmacol Chemother. 1963 Aug;21:1–9. doi: 10.1111/j.1476-5381.1963.tb01497.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. GARVIN J. E., KARNOVSKY M. L. The titration of some phosphatides and related compounds in a non-aqueous medium. J Biol Chem. 1956 Jul;221(1):211–222. [PubMed] [Google Scholar]
  13. HOLLAND W. C., DUNN C. E. Role of the cell membrane and mitochondria in the phenomenon of ion transport in cardiac muscle. Am J Physiol. 1954 Dec;179(3):486–490. doi: 10.1152/ajplegacy.1954.179.3.486. [DOI] [PubMed] [Google Scholar]
  14. ICHIOKA M. The effects of calcium ions upon the size of the action current of single myelinated nerve fibres of the toad. Jpn J Physiol. 1957 Mar 15;7(1):20–28. doi: 10.2170/jjphysiol.7.20. [DOI] [PubMed] [Google Scholar]
  15. ISHIKO N., SATO M. The effect of calcium ions on electrical properties of striated muscle fibres. Jpn J Physiol. 1957 Mar 15;7(1):51–63. doi: 10.2170/jjphysiol.7.51. [DOI] [PubMed] [Google Scholar]
  16. KIRSCHNER L. B. The cation content of phospholipides from swine erythrocytes. J Gen Physiol. 1958 Nov 20;42(2):231–241. doi: 10.1085/jgp.42.2.231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. PAULING L. THE HYDRATE MICROCRYSTAL THEORY OF GENERAL ANESTHESIA. Anesth Analg. 1964 Jan-Feb;43:1–10. [PubMed] [Google Scholar]
  18. RITCHIE J. M., GREENGARD P. On the active structure of local anesthetics. J Pharmacol Exp Ther. 1961 Aug;133:241–245. [PubMed] [Google Scholar]
  19. ROBINS D. C. PHOSPHATIDYLETHANOLAMINE AND LYSOPHOSPHATIDYLETHANOLAMINE. J Pharm Pharmacol. 1963 Nov;15:701–722. doi: 10.1111/j.2042-7158.1963.tb12866.x. [DOI] [PubMed] [Google Scholar]
  20. ROBINS D. C., THOMAS I. L. Physico-chemical experiments with phosphatidyl ethanolamine sols. J Pharm Pharmacol. 1963 Mar;15:157–166. doi: 10.1111/j.2042-7158.1963.tb12765.x. [DOI] [PubMed] [Google Scholar]
  21. ROSANO H. L., SCHULMAN J. H., WEISBUCH J. B. Mechanism of the selective flux of salts and ions through nonaqueous liquid membranes. Ann N Y Acad Sci. 1961 Jun 17;92:457–469. doi: 10.1111/j.1749-6632.1961.tb44995.x. [DOI] [PubMed] [Google Scholar]
  22. SHANES A. M. Electrochemical aspects of physiological and pharmacological action in excitable cells. I. The resting cell and its alteration by extrinsic factors. Pharmacol Rev. 1958 Mar;10(1):59–164. [PubMed] [Google Scholar]
  23. SHANES A. M. Electrochemical aspects of physiological and pharmacological action in excitable cells. II. The action potential and excitation. Pharmacol Rev. 1958 Jun;10(2):165–273. [PubMed] [Google Scholar]
  24. SHANES A. M., FREYGANG W. H., GRUNDFEST H., AMATNIEK E. Anesthetic and calcium action in the voltage-clamped squid giant axon. J Gen Physiol. 1959 Mar 20;42(4):793–802. doi: 10.1085/jgp.42.4.793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. SHANES A. M., GERSHFELD N. L. Interactions of veratrum alkaloids, procaine, and calcium with monolayers of stearic acid and their implications for pharmacological action. J Gen Physiol. 1960 Nov;44:345–363. doi: 10.1085/jgp.44.2.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. STRAUB R. Der Einfluss von Lokalanesthetika auf ionenbedingte Ruhepotentioländerungen von markhaltigen Nervenfasern des Frosches. Arch Int Pharmacodyn Ther. 1956 Sep 1;107(3-4):414–430. [PubMed] [Google Scholar]
  27. TASAKI I. New measurements of the capacity and the resistance of the myelin sheath and the nodal membrane of the isolated frog nerve fiber. Am J Physiol. 1955 Jun;181(3):639–650. doi: 10.1152/ajplegacy.1955.181.3.639. [DOI] [PubMed] [Google Scholar]
  28. TAYLOR R. E. Effect of procaine on electrical properties of squid axon membrane. Am J Physiol. 1959 May;196(5):1071–1078. doi: 10.1152/ajplegacy.1959.196.5.1071. [DOI] [PubMed] [Google Scholar]
  29. TEORELL T. Electrokinetic membrane processes in relation to properties excitable tissues. II. Some theoretical considerations. J Gen Physiol. 1959 Mar 20;42(4):847–863. doi: 10.1085/jgp.42.4.847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. TEORELL T. Electrokinetic membrane processes in relation to properties of excitable tissues. I. Experiments on oscillatory transport phenomena in artificial membranes. J Gen Physiol. 1959 Mar 20;42(4):831–845. doi: 10.1085/jgp.42.4.831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. THESLEFF S. The effect of anesthetic agents on skeletal muscle membrane. Acta Physiol Scand. 1956 Nov 5;37(4):335–349. doi: 10.1111/j.1748-1716.1956.tb01369.x. [DOI] [PubMed] [Google Scholar]
  32. TOBIAS J. M., AGIN D. P., PAWLOWSKI R. Phospholipidcholesterol membrane model. Control of resistance by ions or current flow. J Gen Physiol. 1962 May;45:989–1001. doi: 10.1085/jgp.45.5.989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. TOBIAS J. M. Experimentally altered structure related to function in the lobster axon with an extrapolation to molecular mechanisms in excitation. J Cell Physiol. 1958 Aug;52(1):89–125. doi: 10.1002/jcp.1030520107. [DOI] [PubMed] [Google Scholar]
  34. WARD H. A., FANTL P. Transfer of hydrophilic cations from an aqueous to a lipophilic phase by phosphatidic acids. Arch Biochem Biophys. 1963 Feb;100:338–340. doi: 10.1016/0003-9861(63)90083-3. [DOI] [PubMed] [Google Scholar]
  35. WEBER A., HERZ R., REISS I. On the mechanism of the relaxing effect of fragmented sarcoplasmic reticulum. J Gen Physiol. 1963 Mar;46:679–702. doi: 10.1085/jgp.46.4.679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. WEIDMANN S. Effects of calcium ions and local anesthetics on electrical properties of Purkinje fibres. J Physiol. 1955 Sep 28;129(3):568–582. doi: 10.1113/jphysiol.1955.sp005379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. WOOLLEY D. W., CAMPBELL N. K. Tissue lipids as ion exchangers for cations and the relationship to physiological processes. Biochim Biophys Acta. 1962 Feb 26;57:384–385. doi: 10.1016/0006-3002(62)91137-x. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of General Physiology are provided here courtesy of The Rockefeller University Press

RESOURCES