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Antidepressants inhibit Nav1.3, Nav1.7, and Nav1.8 neuronal voltage-gated sodium channels more potently than Nav1.2 and Nav1.6 channels expressed in Xenopus oocytes

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Abstract

Tricyclic antidepressants (TCAs) and duloxetine are used to treat neuropathic pain. However, the mechanisms underlying their analgesic effects remain unclear. Although many investigators have shown inhibitory effects of antidepressants on voltage-gated sodium channels (Nav) as a possible mechanism of analgesia, to our knowledge, no one has compared effects on the diverse variety of sodium channel α subunits. We investigated the effects of antidepressants on sodium currents in Xenopus oocytes expressing Nav1.2, Nav1.3, Nav1.6, Nav1.7, and Nav1.8 with a β1 subunit by using whole-cell, two-electrode, voltage clamp techniques. We also studied the role of the β3 subunit on the effect of antidepressants on Nav1.3. All antidepressants inhibited sodium currents in an inactivated state induced by all five α subunits with β1. The inhibitory effects were more potent for Nav1.3, Nav1.7, and Nav1.8, which are distributed in dorsal root ganglia, than Nav1.2 and Nav1.6, which are distributed primarily in the central nervous system. The effect of amitriptyline on Nav1.7 with β1 was most potent with a half-maximal inhibitory concentration (IC50) 4.6 μmol/L. IC50 for amitriptyline on Nav1.3 coexpressed with β1 was lowered from 8.4 to 4.5 μmol/L by coexpression with β3. Antidepressants predominantly inhibited the sodium channels expressed in dorsal root ganglia, and amitriptyline has the most potent inhibitory effect. This is the first evidence, to our knowledge, showing the diverse effects of antidepressants on various α subunits. Moreover, the β3 subunit appears important for inhibition of Nav1.3. These findings may aid better understanding of the mechanisms underlying the pain relieving effects of antidepressants.

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Acknowledgements

Funding

This study was supported by a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science, 25462462 (to Takeyoshi Sata).

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Authors and Affiliations

  1. Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu, Fukuoka, 807-8555, Japan

    Takafumi Horishita, Dan Okura, Reiko Horishita, Tomoko Minami, Yuichi Ogata, Takeyoshi Sata & Takashi Kawasaki

  2. Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu, Fukuoka, 807-8555, Japan

    Nobuyuki Yanagihara

  3. Department of Occupational Toxicology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu, Fukuoka, 807-8555, Japan

    Susumu Ueno

  4. Department of Molecular Pathology & Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan

    Yuka Sudo

  5. Cancer Pathophysiology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuouku, Tokyo, 104-0045, Japan

    Yasuhito Uezono

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  1. Takafumi Horishita
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  2. Nobuyuki Yanagihara
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  3. Susumu Ueno
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  4. Dan Okura
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  5. Reiko Horishita
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  7. Yuichi Ogata
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  8. Yuka Sudo
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  9. Yasuhito Uezono
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  10. Takeyoshi Sata
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  11. Takashi Kawasaki
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Correspondence to Takafumi Horishita.

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This study was approved by the Animal Research Committee of the University of Occupational and Environmental Health, Kitakyushu, Japan.

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Horishita, T., Yanagihara, N., Ueno, S. et al. Antidepressants inhibit Nav1.3, Nav1.7, and Nav1.8 neuronal voltage-gated sodium channels more potently than Nav1.2 and Nav1.6 channels expressed in Xenopus oocytes. Naunyn-Schmiedeberg's Arch Pharmacol 390, 1255–1270 (2017). https://doi.org/10.1007/s00210-017-1424-x

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  • DOI: https://doi.org/10.1007/s00210-017-1424-x

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