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OtherTOXICOLOGY

Lidocaine Toxicity in Primary Afferent Neurons from the Rat

Michael S. Gold, David B. Reichling, Karl F. Hampl, Kenneth Drasner and Jon D. Levine
Journal of Pharmacology and Experimental Therapeutics May 1998, 285 (2) 413-421;
Michael S. Gold
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David B. Reichling
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Karl F. Hampl
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Kenneth Drasner
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Abstract

Evidence from both clinical studies and animal models suggests that the local anesthetic, lidocaine, is neurotoxic. However, the mechanism of lidocaine-induced toxicity is unknown. To test the hypothesis that toxicity results from a direct action of lidocaine on sensory neurons we performed in vitro histological, electrophysiological and fluorometrical experiments on isolated dorsal root ganglion (DRG) neurons from the adult rat. We observed lidocaine-induced neuronal death after a 4-min exposure of DRG neurons to lidocaine concentrations as low as 30 mM. Consistent with an excitotoxic mechanism of neurotoxicity, lidocaine depolarized DRG neurons at concentrations that induced cell death (EC50 = 14 mM). This depolarization occurred even though voltage-gated sodium currents and action potentials were blocked effectively at much lower concentrations. (EC50 values for lidocaine-induced block of tetrodotoxin-sensitive and -resistant voltage-gated sodium currents were 41 and 101 μM, respectively.) At concentrations similar to those that induced neurotoxicity and depolarization, lidocaine also induced an increase in the concentration of intracellular Ca++ ions ([Ca++]i; EC50 = 21 mM)via Ca++ influx through the plasma membrane as well as release of Ca++ from intracellular stores. Finally, lidocaine-induced neurotoxicity was attenuated significantly when lidocaine was applied in the presence of nominally Ca++-free bath solution to DRG neurons preloaded with 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA). Our results indicate: 1) that lidocaine is neurotoxic to sensory neurons; 2) that toxicity results from a direct action on sensory neurons; and 3) that a lidocaine-induced increase in intracellular Ca++is a mechanism of lidocaine-induced neuronal toxicity.

Footnotes

  • Send reprint requests to: Michael S. Gold, Ph.D., University of Maryland at Baltimore, Department of OCBS, Room 5-A-12, Dental School, 666 W. Baltimore Street, Baltimore, MD 21201.

  • ↵1 This work was supported by National Institutes of Health grants NS21647, NS07265, NS07101 and GM51887.

  • Abbreviations:
    BAPTA
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
    DMSO
    dimethyl sulfoxide
    DRG
    dorsal root ganglion
    HEPES
    N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
    PBS
    phosphate-buffered saline
    TTX-R INa
    tetrodotoxin-resistant sodium current
    TTX-S INa
    tetrodotoxin-sensitive sodium current
    • Received July 16, 1997.
    • Accepted January 5, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 2
1 May 1998
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OtherTOXICOLOGY

Lidocaine Toxicity in Primary Afferent Neurons from the Rat

Michael S. Gold, David B. Reichling, Karl F. Hampl, Kenneth Drasner and Jon D. Levine
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 413-421;

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OtherTOXICOLOGY

Lidocaine Toxicity in Primary Afferent Neurons from the Rat

Michael S. Gold, David B. Reichling, Karl F. Hampl, Kenneth Drasner and Jon D. Levine
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 413-421;
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