Anxiolytic effects of the novel α2δ ligand mirogabalin in a rat model of chronic constriction injury, an experimental model of neuropathic pain
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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.
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.
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.
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.
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.
KeywordsMirogabalin α2δ subunit Voltage-gated calcium channel Neuropathic pain Allodynia Anxiety Depression Analgesic Chronic constriction injury Elevated plus maze
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.
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.
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