Peripheral administration of SB223412, a selective neurokinin-3 receptor antagonist, suppresses pulsatile luteinizing hormone secretion by acting on the gonadotropin-releasing hormone pulse generator in estrogen-treated ovariectomized female goats

  • SASAKI Takuya
    Laboratory of Animal Production Science, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
  • SONODA Tomoya
    Laboratory of Animal Production Science, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
  • TATEBAYASHI Ryoki
    Laboratory of Animal Production Science, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
  • KITAGAWA Yuri
    Laboratory of Animal Production Science, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
  • OISHI Shinya
    Laboratory of Bioorganic Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
  • YAMAMOTO Koki
    Laboratory of Bioorganic Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
  • FUJII Nobutaka
    Laboratory of Bioorganic Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
  • INOUE Naoko
    Laboratory of Reproductive Science, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
  • UENOYAMA Yoshihisa
    Laboratory of Reproductive Science, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
  • TSUKAMURA Hiroko
    Laboratory of Reproductive Science, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
  • MAEDA Kei-ichiro
    Laboratory of Theriogenology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan
  • MATSUDA Fuko
    Laboratory of Theriogenology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan
  • MORITA Yasuhiro
    Laboratory of Animal Production Science, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
  • MATSUYAMA Shuichi
    Laboratory of Animal Production Science, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
  • OHKURA Satoshi
    Laboratory of Animal Production Science, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan

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Abstract

<p> Accumulating evidence suggests that KNDy neurons located in the hypothalamic arcuate nucleus (ARC), which are reported to express kisspeptin, neurokinin B, and dynorphin A, are indispensable for the gonadotropin-releasing hormone (GnRH) pulse generation that results in rhythmic GnRH secretion. The aims of the present study were to investigate the effects of peripheral administration of the neurokinin 3 receptor (NK3R/TACR3, a receptor for neurokinin B) antagonist, SB223412, on GnRH pulse-generating activity and pulsatile luteinizing hormone (LH) secretion in ovariectomized Shiba goats treated with luteal phase levels of estrogen. The NK3R antagonist was infused intravenously for 4 h {0.16 or 1.6 mg/(kg body weight [BW]·4 h)} during which multiple unit activity (MUA) in the ARC was recorded, an electrophysiological technique commonly employed to monitor GnRH pulse generator activity. In a separate experiment, the NK3R antagonist (40 or 200 mg/[kg BW·day]) was administered orally for 7 days to determine whether the NK3R antagonist could modulate pulsatile LH secretion when administered via the oral route. Intravenous infusion of the NK3R antagonist significantly increased the interval of episodic bursts of MUA compared with that of the controls. Oral administration of the antagonist for 7 days also significantly prolonged the interpulse interval of LH pulses. The results of this study demonstrate that peripheral administration of an NK3R antagonist suppresses pulsatile LH secretion by acting on the GnRH pulse generator, suggesting that NK3R antagonist administration could be used to modulate reproductive functions in ruminants.</p>

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