Abstract
Glycyrrhiza extract has been used for the treatment of oral and gastric ulcers, but the analgesic mechanism remains unknown. In the present study, we investigated the effects of isoliquiritigenin, an active ingredient of Glycyrrhiza, on Nav channels in vitro and nociceptive behaviors in vivo. In an autopatch-clamp study, isoliquiritigenin inhibited the currents of Nav1.1, Nav1.3, Nav1.6, Nav1.7, and Nav1.8 in a channel expression system. In small- and medium-sized cultured trigeminal ganglion neurons, the compound suppressed Nav currents in many neurons (78%) and Kv currents in all neurons, dose-dependently. In current-clamp mode, isoliquiritigenin blocked action potential generation in many neurons (64%), but it conversely accelerated action potential generation in the remaining neurons. The opposing effects on action potentials were reproduced in a computational simulation of a modified Hodgkin-Huxley-based model, based on the electrophysiological data. In behavioral experiments, local treatment with isoliquiritigenin suppressed nociceptive behaviors in response to oral ulcer development or nociceptive TRP channel agonists in the oral mucosa and hind paw. These results suggest that isoliquiritigenin exerts an analgesic effect predominantly via inhibitory action on Nav channels on sensory nociceptive fibers. This pharmacological mechanism indicates that isoliquiritigenin is useful for pain relief and provides scientific evidence for Glycyrrhiza at the ingredient level.
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Abbreviations
- CFA:
-
Complete Freund’s adjuvant
- OUM:
-
Oral ulcerative mucositis
- ILG:
-
Isoliquiritigenin
- LG:
-
Liquiritigenin
- BC:
-
Baicalein
- WGN:
-
Wogonin
- BBR:
-
Berberine
- COP:
-
Coptisine
- CHO:
-
Chinese hamster ovary
- HEK293:
-
Human embryonic kidney 293
- FLIPR:
-
Fluorescence imaging plate reader
- Lido:
-
Lidocaine
- AITC:
-
Allyl isothiocyanate
- TG:
-
Trigeminal ganglion
- CPS:
-
Capsaicin
- PST:
-
Partial sciatic nerve transection
- HOK:
-
Human oral keratinocytes
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Acknowledgments
The authors are grateful to Miho Nitta for her technical assistance.
Funding
This work was funded by Tsumura & Co. (Tokyo, Japan) and a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (JSPS KAKENHI 25861760 and 15K20377). Y.O. is an employee of Tsumura & Co. K.O. and S.H. received grant support from Tsumura & Co.
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The first author, Y.M., performed most behavioral experiments and all of the patch-clamp recordings from cultured TG neurons. S.H. prepared the rat OUM model and administered the drugs to ensure that the first author, Y.M., was blinded to the conditions of the behavioral experiments. S.K. prepared the rat neuropathic pain model. Y.O. organized the channel-screening test. I.U. and the sixth author Y.M. designed the experiments and supervised the research. The corresponding author, K.O., designed all experiments and organized the study. All authors have read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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Y.O is an employee of Tsumura & Co.
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All animal experiments were approved by the Animal Experiment Committee of Kyushu Dental University (approval nos. 18-002 and 18-006).
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Miyamura, Y., Hitomi, S., Omiya, Y. et al. Isoliquiritigenin, an active ingredient of Glycyrrhiza, elicits antinociceptive effects via inhibition of Nav channels. Naunyn-Schmiedeberg's Arch Pharmacol 394, 967–980 (2021). https://doi.org/10.1007/s00210-020-02030-w
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DOI: https://doi.org/10.1007/s00210-020-02030-w