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A mammalian gonadotropin-inhibitory hormone homolog RFamide-related peptide 3 regulates pain and anxiety in mice

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Abstract

RFamide-related peptide (RFRP) is a homologous neuropeptide to gonadotropin-inhibitory hormone (GnIH), which is a hypothalamic neuropeptide that negatively regulates the hypothalamic-pituitary–gonadal axis. RFRP/GnIH is thought to be the mediator of stress because various stressors increase RFRP/GnIH mRNA expression and/or RFRP/GnIH neuronal activities. RFRP/GnIH may also directly regulate behavior, because RFRP/GnIH neuronal fibers and RFRP/GnIH receptor are widely expressed in the brain. Here, we create a RFRP/GnIH knockout (GnIH-KO) mice and conduct various behavioral tests. Dense RFRP/GnIH neuronal fibers are located in the limbic system and broad areas in the thalamus, hypothalamus, and midbrain in wild-type mice but not in RFRP/GnIH-KO mice. Spatial working memory is not improved in GnIH-KO mice as shown by Y-maze test. GnIH-KO mice perform intensive wheel running exercise for several hours after light-off. Hot plate test shows that GnIH-KO mice have decreased sensitivity to pain and central administration of RFRP3 to GnIH-KO mice recovers pain sensitivity. Elevated plus maze test shows that GnIH-KO mice have decreased level of anxiety and central administration of RFRP3 to GnIH-KO mice recovers anxiety level. These results indicate that RFRP3 regulates pain and anxiety in mice. RFRP3 may be involved in the negative regulation of spontaneous activity in addition to negatively regulating the reproductive neuroendocrine axis in stressful conditions.

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Acknowledgements

I sincerely thank Professor Kazuyoshi Tsutsui (Hiroshima University) who supported this study but passed away on September 16, 2021. I also thank Sonoko Okada, Misato Narihiro, Daiki Yamazaki, Ren Taguchi, Shiho Takezawa, Yuri Sato, and Dr. Yu Tahara (Waseda University) for their technical assistances, and Dr. Takefumi Kikusui (Azabu University) for his guidance of behavioral experiments. I thank RIKEN BRC, Dr. S. Noguchi (Meiji Institute of Health Science, Meiji Milk Products Co., Ltd.), and Dr. K. Nishimura (Kanagawa Academy of Science and Technology) for providing Nestin-cre system mouse (RBRC02412).

Funding

This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan (23570091 to TU; 15207007, 16086206, 18107002, 22132004, and 22227002 to Kazuyoshi Tsutsui).

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  1. International Cancer Laboratory Co., Ltd, Chuo-ku, Tokyo, 104-0041, Japan

    Takayoshi Ubuka

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TU designed the study, performed experiments, and wrote the manuscript.

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Correspondence to Takayoshi Ubuka.

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The experimental protocols were approved by Waseda University licensing committees for genetic modification (WD17-015) and animal experiments (2017-A005). All procedures were performed in accordance with the Waseda University Safety Management Rules for Biological Experiment.

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Ubuka, T. A mammalian gonadotropin-inhibitory hormone homolog RFamide-related peptide 3 regulates pain and anxiety in mice. Cell Tissue Res 391, 159–172 (2023). https://doi.org/10.1007/s00441-022-03695-w

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