Abstract
Mirogabalin, a novel ligand for the α2δ subunit of voltage-gated calcium channels, is under the development for the treatment of neuropathic pain. Mirogabalin specifically and potently binds to α2δ subunits, and it shows analgesic effects in both peripheral and central neuropathic pain models in rats. To expand pharmacological findings on mirogabalin and provide additional information of its potential for chronic pain therapy, we examined the effects of mirogabalin in 2 experimental models of fibromyalgia, namely, the intermittent cold stress model (ICS model) and the unilateral intramuscular acidic saline injection model (Sluka model). To induce chronic mechanical hypersensitivity, mice were placed under ICS conditions for 3 days, whereas rats were injected twice with acidic saline (pH 4) into the gastrocnemius muscle in a 4-day interval. The pain sensitivity was evaluated by the von Frey test. Long-lasting increases in pain response score or decreases in pain threshold to the von Frey stimulation were observed in both the ICS and Sluka models. Mirogabalin (1, 3, or 10 mg/kg, p.o.) dose-dependently alleviated the mechanical hypersensitivity, with significant effects persisting at 6 or 8 h following administration. The standard α2δ ligand, pregabalin (30 mg/kg, p.o.), also significantly reduced the mechanical hypersensitivity. In summary, mirogabalin showed analgesic effects in the ICS model mice and in the Sluka model rats. Therefore, mirogabalin may have the potential to provide effective pain relief in patients with fibromyalgia.
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Acknowledgments
We would like to thank Kousei Shimada and Asuka Kawamura for the chemical synthesis and Michiharu Yoshiike and Jun Harada for their expertise in the statistical analyses. We would also like to express our sincere thanks to the Scientific Language Co., Ltd. (Ibaraki, Japan) for reviewing and editing this manuscript.
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SY, MKato, and YK conceived and designed the research. KS, SY, MKato, MKano, YD, and NA performed experiments and analyzed the data. YK wrote the manuscript. All authors read and approved the manuscript.
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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 Guideline of the Institutional Animal Care and Use Committee of Daiichi Sankyo Co., Ltd. This article does not contain any studies with human participants performed by any of the authors.
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KS, SY, MKato, and MKano are employees of Nihon Bioresearch Inc., while YD, NA, and YK are employees of Daiichi Sankyo Co., Ltd. This study was sponsored by Daiichi Sankyo Co., Ltd.
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Saeki, K., Yasuda, Si., Kato, M. et al. Analgesic effects of mirogabalin, a novel ligand for α2δ subunit of voltage-gated calcium channels, in experimental animal models of fibromyalgia. Naunyn-Schmiedeberg's Arch Pharmacol 392, 723–728 (2019). https://doi.org/10.1007/s00210-019-01628-z
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DOI: https://doi.org/10.1007/s00210-019-01628-z