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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Inhibition of Neuronal Na+ Channels by Antidepressant Drugs

Joseph J. Pancrazio, Ganesan L. Kamatchi, Amy K. Roscoe and Carl Lynch III
Journal of Pharmacology and Experimental Therapeutics January 1998, 284 (1) 208-214;
Joseph J. Pancrazio
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Ganesan L. Kamatchi
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Amy K. Roscoe
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Carl Lynch III
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Abstract

Although tricyclic antidepressant (TCA) blockade of cardiac Na+ channels is appreciated, actions on neuronal Na+ channels are less clear. Therefore, the effects of TCAs (amitriptyline, doxepin and desipramine) as well as trazadone and fluoxetine on voltage-gated Na+ current (INa) were examined in bovine adrenal chromaffin cells using the whole-cell patch-clamp method. Amitriptyline produced concentration-dependent depression of peak INa evoked from a holding potential of −80 mV with KD value of 20.2 μM and a Hill coefficient of 1.2. Although 20 μM amitriptyline induced no change in the rate or voltage dependence of INaactivation, steady-state inactivation demonstrated a 15-mV hyperpolarizing shift. Similar results were observed for doxepin and desipramine. This shift in steady-state inactivation was associated with a slowed rate of recovery from the inactivated state. Contrasting results were observed with the atypical antidepressants: while 20 μM fluoxetine depressed peak INa by 61% and caused a 7-mV hyperpolarizing shift in steady-state inactivation, 100 μM trazodone decreased peak INa by only 19% and caused only a 3-mV shift. Although the magnitude of fluoxetine effects was similar to those of the TCAs, the onset of fluoxetine effects was substantially slower than for amitriptyline. In voltage-clamp and current-clamp measurements from neonatal rat dorsal root ganglion neurons, 20 μM amitriptyline decreased INa by 52% and depressed action potential dynamics consistent with enhanced Na+ channel inactivation. The effects of the TCAs on INa are similar to local anesthetic behavior and could contribute to certain analgesic actions.

Footnotes

  • Send reprint requests to: Carl Lynch III, M.D., Ph.D., Department of Anesthesiology, Box 10010, University of Virginia, Health Sciences Center, Charlottesville, VA 22906-0010. E-mail:cl7y{at}virginia.edu

  • ↵1 This study was supported in part by National Institutes of Health Research Grant GM31144 (C.L.).

  • ↵2 Present address: Code 6900, Naval Research Laboratory, Washington, DC 20375.

  • Abbreviations:
    AP
    action potential
    CSF
    cerebrospinal fluid
    DRG
    dorsal root ganglion
    dV/dtmax
    maximum rate of depolarization
    INa
    sodium current
    I-V
    current voltage
    VH
    holding potential
    LA
    local anesthetic
    EGTA
    ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
    HEPES
    4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
    TCA
    tricyclic antidepressant
    • Received April 29, 1997.
    • Accepted September 15, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 1
1 Jan 1998
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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Inhibition of Neuronal Na+ Channels by Antidepressant Drugs

Joseph J. Pancrazio, Ganesan L. Kamatchi, Amy K. Roscoe and Carl Lynch
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 208-214;

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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Inhibition of Neuronal Na+ Channels by Antidepressant Drugs

Joseph J. Pancrazio, Ganesan L. Kamatchi, Amy K. Roscoe and Carl Lynch
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 208-214;
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