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Anxiolytic effects of the novel α2δ ligand mirogabalin in a rat model of chronic constriction injury, an experimental model of neuropathic pain

  • Hiroyasu Murasawa
  • Hiroyuki Kobayashi
  • Kensuke Saeki
  • Yutaka KitanoEmail author
Original Investigation
  • 23 Downloads

Abstract

Rationale

Psychiatric disorders such as anxiety and depression are frequently observed in neuropathic pain patients, and negatively impact their quality of life. Mirogabalin is a novel ligand for the α2δ subunit of voltage-gated calcium channels and has unique binding characteristics to α2δ subunits and potent and long-lasting analgesic effects in neuropathic pain models.

Objectives

To provide further information on the pharmacological profile of mirogabalin and its utility for chronic pain therapy, we investigated its anxiolytic effects in an experimental animal model for neuropathic pain.

Methods

In chronic constriction injury (CCI) model rats, mechanical hypersensitivity was determined by the von Frey test. Anxiety- and depression-related behaviours were evaluated using the elevated plus maze test and forced swimming test, respectively.

Results

CCI model rats showed sustained tactile allodynia followed by anxiety-related behaviours, not depression-related behaviours. The tactile allodynia (significant decreases in paw withdrawal threshold) developed within 2 weeks after model preparation, whereas the anxiety-related behaviours (significant decreases in the number of entries and time spent in open arms and significant increases in time spent in closed arms) were observed at 5 weeks but not 4 weeks after model preparation. Single oral administration of mirogabalin (3 or 10 mg/kg) dose-dependently alleviated the above-mentioned anxiety-related behaviours and tactile allodynia.

Conclusions

CCI model rats showed anxiety-related behaviours in a time-dependent manner in the elevated plus maze test. Mirogabalin alleviated both the anxiety-related behaviours and tactile allodynia in CCI model rats. Mirogabalin may provide effective anxiety relief as well as pain relief in patients with neuropathic pain.

Keywords

Mirogabalin α2δ subunit Voltage-gated calcium channel Neuropathic pain Allodynia Anxiety Depression Analgesic Chronic constriction injury Elevated plus maze 

Notes

Acknowledgements

We thank Asuka Kawamura and Kousei Shimada for help with the chemical synthesis. We also thank Miki Sugiyama, Katsuhiro Higuchi and Yuri Noda for their expertise in the experiments. In addition, we thank Masami Kato, Mayumi Kano, Jun Harada, Mitsuhiro Makino, Kaori Ito, Yuki Domon, Naohisa Arakawa and Kazufumi Kubota for all of their support in this study. Finally, we wish to express our gratitude to Scientific Language Co., Ltd. (Ibaraki, Japan), for reviewing and editing this manuscript.

Author contributions

HM and YK conceived and designed the research. HM, HK and KS performed the experiments and analysed the data. HM and YK wrote the manuscript. All authors read and approved the manuscript.

Compliance with ethical standards

All animal experiments were conducted in accordance with the Guidelines for Management and Welfare of Experimental Animals (Hashima Laboratory, Nihon Bioresearch Inc.; April 2, 2007, modified on August 27, 2010), and the Guidelines of the Institutional Animal Care and Use Committee of Daiichi Sankyo Co., Ltd. This article does not describe any studies with human participants performed by any of the authors.

Conflict of interest

HM, HK and KS are employees of Nihon Bioresearch Inc., while YK is an employee of Daiichi Sankyo Co., Ltd. This study was sponsored by Daiichi Sankyo Co., Ltd.

Supplementary material

213_2019_5356_MOESM1_ESM.pdf (56 kb)
ESM 1 (PDF 55.7 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Hiroyasu Murasawa
    • 1
  • Hiroyuki Kobayashi
    • 1
  • Kensuke Saeki
    • 1
  • Yutaka Kitano
    • 2
    Email author
  1. 1.Hashima LaboratoryNihon Bioresearch Inc.GifuJapan
  2. 2.Pain & Neuroscience LaboratoriesDaiichi Sankyo Co.TokyoJapan

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