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Research ArticleNeuropharmacology

Central Mechanisms of Menthol-Induced Analgesia

Rong Pan, Yuzhen Tian, Ruby Gao, Haitao Li, Xianguo Zhao, James E. Barrett and Huijuan Hu
Journal of Pharmacology and Experimental Therapeutics December 2012, 343 (3) 661-672; DOI: https://doi.org/10.1124/jpet.112.196717
Rong Pan
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (R.P., Y.T., R.G., H.L., J.E.B., H.H.); Center for Teaching and Experiment, Nanjing University of Traditional Chinese Medicine, Nanjing, China (H.L.); and PharmaOn, LLC, Monmouth Junction, New Jersey (X.Z.)
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Yuzhen Tian
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (R.P., Y.T., R.G., H.L., J.E.B., H.H.); Center for Teaching and Experiment, Nanjing University of Traditional Chinese Medicine, Nanjing, China (H.L.); and PharmaOn, LLC, Monmouth Junction, New Jersey (X.Z.)
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Ruby Gao
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (R.P., Y.T., R.G., H.L., J.E.B., H.H.); Center for Teaching and Experiment, Nanjing University of Traditional Chinese Medicine, Nanjing, China (H.L.); and PharmaOn, LLC, Monmouth Junction, New Jersey (X.Z.)
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Haitao Li
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (R.P., Y.T., R.G., H.L., J.E.B., H.H.); Center for Teaching and Experiment, Nanjing University of Traditional Chinese Medicine, Nanjing, China (H.L.); and PharmaOn, LLC, Monmouth Junction, New Jersey (X.Z.)
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Xianguo Zhao
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (R.P., Y.T., R.G., H.L., J.E.B., H.H.); Center for Teaching and Experiment, Nanjing University of Traditional Chinese Medicine, Nanjing, China (H.L.); and PharmaOn, LLC, Monmouth Junction, New Jersey (X.Z.)
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James E. Barrett
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (R.P., Y.T., R.G., H.L., J.E.B., H.H.); Center for Teaching and Experiment, Nanjing University of Traditional Chinese Medicine, Nanjing, China (H.L.); and PharmaOn, LLC, Monmouth Junction, New Jersey (X.Z.)
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Huijuan Hu
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (R.P., Y.T., R.G., H.L., J.E.B., H.H.); Center for Teaching and Experiment, Nanjing University of Traditional Chinese Medicine, Nanjing, China (H.L.); and PharmaOn, LLC, Monmouth Junction, New Jersey (X.Z.)
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Abstract

Menthol is one of the most commonly used chemicals in our daily life, not only because of its fresh flavor and cooling feeling but also because of its medical benefit. Previous studies have suggested that menthol produces analgesic action in acute and neuropathic pain through peripheral mechanisms. However, the central actions and mechanisms of menthol remain unclear. Here, we report that menthol has direct effects on the spinal cord. Menthol decreased both ipsilateral and contralateral pain hypersensitivity induced by complete Freund's adjuvant in a dose-dependent manner. Menthol also reduced both first and second phases of formalin-induced spontaneous nocifensive behavior. We then identified the potential central mechanisms underlying the analgesic effect of menthol. In cultured dorsal horn neurons, menthol induced inward and outward currents in a dose-dependent manner. The menthol-activated current was mediated by Cl− and blocked by bicuculline, suggesting that menthol activates γ-aminobutyric acid type A receptors. In addition, menthol blocked voltage-gated sodium channels and voltage-gated calcium channels in a voltage-, state-, and use-dependent manner. Furthermore, menthol reduced repetitive firing and action potential amplitude, decreased neuronal excitability, and blocked spontaneous synaptic transmission of cultured superficial dorsal horn neurons. Liquid chromatography/tandem mass spectrometry analysis of brain menthol levels indicated that menthol was rapidly concentrated in the brain when administered systemically. Our results indicate that menthol produces its central analgesic action on inflammatory pain probably via the blockage of voltage-gated Na+ and Ca2+ channels. These data provide molecular and cellular mechanisms by which menthol decreases neuronal excitability, therefore contributing to menthol-induced central analgesia.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.196717.

  • ABBREVIATIONS:

    TRP
    transient receptor potential
    CFA
    complete Freund's adjuvant
    DMSO
    dimethyl sulfoxide
    DRG
    dorsal root ganglion
    EPSC
    excitatory postsynaptic current
    GABAA
    γ-aminobutyric acid type A
    HPLC
    high-performance liquid chromatography
    ICa
    calcium current
    INa
    sodium current
    I-V
    current-voltage
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    TTX
    tetrodotoxin.

  • Received May 22, 2012.
  • Accepted August 29, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 3
1 Dec 2012
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Research ArticleNeuropharmacology

Mechanisms of Menthol's Action

Rong Pan, Yuzhen Tian, Ruby Gao, Haitao Li, Xianguo Zhao, James E. Barrett and Huijuan Hu
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 661-672; DOI: https://doi.org/10.1124/jpet.112.196717

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Research ArticleNeuropharmacology

Mechanisms of Menthol's Action

Rong Pan, Yuzhen Tian, Ruby Gao, Haitao Li, Xianguo Zhao, James E. Barrett and Huijuan Hu
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 661-672; DOI: https://doi.org/10.1124/jpet.112.196717
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