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Research ArticleNEUROPHARMACOLOGY

The Anticonvulsant, Antihyperalgesic Agent Gabapentin Is an Agonist at Brain γ-Aminobutyric Acid Type B Receptors Negatively Coupled to Voltage-Dependent Calcium Channels

Sandrine Bertrand, Gordon Y. K. Ng, Maya Gadhvi Purisai, Shannyn E. Wolfe, Mathew W. Severidt, Dominique Nouel, Richard Robitaille, Malcolm J. Low, Gary P. O'Neill, Kathleen Metters, Jean-Claude Lacaille, Bibie M. Chronwall and Stephen J. Morris
Journal of Pharmacology and Experimental Therapeutics July 2001, 298 (1) 15-24;
Sandrine Bertrand
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Gordon Y. K. Ng
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Maya Gadhvi Purisai
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Shannyn E. Wolfe
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Mathew W. Severidt
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Dominique Nouel
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Richard Robitaille
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Malcolm J. Low
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Gary P. O'Neill
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Kathleen Metters
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Jean-Claude Lacaille
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Bibie M. Chronwall
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Stephen J. Morris
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Abstract

Gabapentin (Neurontin, Pfizer Global R & D) is a novel anticonvulsant, antihyperalgesic, and antinociceptive agent with a poorly understood mechanism of action. In this study, we show that gabapentin (EC50 2 μM) inhibited up to 70 to 80% of the total K+-evoked Ca2+ influx via voltage-dependent calcium channels (VD-CCs) in a mouse pituitary intermediate melanotrope clonal mIL-tsA58 (mIL) cell line. mIL cells endogenously express only γ-aminobutyric acid type B (GABAB) gb1a-gb2 receptors. Moreover, activity of the agonist gabapentin was dose dependently and completely blocked with the GABAB antagonist CGP55845 and was nearly identical to the prototypic GABAB agonist baclofen in both extent and potency. Antisense knockdown of gb1a also completely blocked gabapentin activity, while gb1b antisense and control oligonucleotides had no effect, indicating that gabapentin inhibition of membrane Ca2+ mobilization in mIL cells was dependent on a functional GABAB (gb1a-gb2) heterodimer receptor. In addition, during combined whole cell recording and multiphoton Ca2+ imaging in hippocampal neurons in situ, gabapentin significantly inhibited in a dose-dependent manner subthreshold soma depolarizations and Ca2+ responses evoked by somatic current injection. Furthermore, gabapentin almost completely blocked Ca2+ action potentials and Ca2+ responses elicited by suprathreshold current injection. However, larger current injection overcame this inhibition of Ca2+ action potentials suggesting that gabapentin did not predominantly affect L-type Ca2+ channels. The depressant effect of gabapentin on Ca2+ responses was coupled to the activation of neuronal GABAB receptors since they were blocked by CGP55845, and baclofen produced similar effects. Thus gabapentin activation of neuronal GABAB gb1a-gb2 receptors negatively coupled to VD-CCs can be a potentially important therapeutic mechanism of action of gabapentin that may be linked to inhibition of neurotransmitter release in some systems.

Footnotes

  • ↵1 Co-first authors.

  • S.B. was supported by a postdoctoral fellowship from the Savoy Foundation and a Cordeau/Servier fellowship from the Center de Recherche en Sciences Neurologiques, Université de Montréal. The work in the laboratory of S.J.M. was supported by the Loeb Charitable Foundation, National Science Foundation Grant IBN 9907571, and University of Missouri Research Board (B.M.C.). The work in the laboratory of J.-C. L. was supported by the Canadian Institutes of Health Research, the Fonds de la Recherche en Santé du Québec (FRSQ), a Research Center grant from the Fonds pour la Formation de Chercheurs et l'Aide àla Recherche (FCAR) to the Groupe de Recherche sur le Système Nerveux Central (GRSNC) and an Équipe de Recherche grant from the FCAR.

  • Abbreviations:
    GABA
    γ-amino-butyric acid
    gb1
    GABABR1 receptor subunit
    gb2
    GABABR2 receptor subunit
    VD-CC
    voltage-dependent calcium channel
    mIL
    mIL-tsA58
    GIRK
    inwardly rectifying K+ channel
    AM
    acetoxymethyl
    DMEM
    Dulbecco's modified Eagle's medium
    pHi
    intracellular pH
    [Ca2+]i
    intracellular calcium
    ADN
    antisense deoxynucleotide
    TTX
    tetrodotoxin
    • Received January 19, 2001.
    • Accepted March 20, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 1
1 Jul 2001
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Research ArticleNEUROPHARMACOLOGY

The Anticonvulsant, Antihyperalgesic Agent Gabapentin Is an Agonist at Brain γ-Aminobutyric Acid Type B Receptors Negatively Coupled to Voltage-Dependent Calcium Channels

Sandrine Bertrand, Gordon Y. K. Ng, Maya Gadhvi Purisai, Shannyn E. Wolfe, Mathew W. Severidt, Dominique Nouel, Richard Robitaille, Malcolm J. Low, Gary P. O'Neill, Kathleen Metters, Jean-Claude Lacaille, Bibie M. Chronwall and Stephen J. Morris
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 15-24;

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Research ArticleNEUROPHARMACOLOGY

The Anticonvulsant, Antihyperalgesic Agent Gabapentin Is an Agonist at Brain γ-Aminobutyric Acid Type B Receptors Negatively Coupled to Voltage-Dependent Calcium Channels

Sandrine Bertrand, Gordon Y. K. Ng, Maya Gadhvi Purisai, Shannyn E. Wolfe, Mathew W. Severidt, Dominique Nouel, Richard Robitaille, Malcolm J. Low, Gary P. O'Neill, Kathleen Metters, Jean-Claude Lacaille, Bibie M. Chronwall and Stephen J. Morris
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 15-24;
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