Laboratory of Theriogenology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
Laboratory of Animal Production Science, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
Neurosci Lett. 2024 Aug 10;837:137918. doi: 10.1016/j.neulet.2024.137918. Epub 2024 Aug 3.
Neurons co-expressing kisspeptin, neurokinin B, and dynorphin A (KNDy neurons), located in the arcuate nucleus (ARC) of the hypothalamus, are indicated to be the gonadotropin-releasing hormone (GnRH) pulse generator. Dynorphin A is reported to suppress GnRH pulse generator activity. Nalfurafine is a selective agonist of the κ-opioid receptor (KOR), a receptor for dynorphin A, clinically used as an anti-pruritic drug. This study aimed to evaluate the effects of nalfurafine on GnRH pulse generator activity and luteinizing hormone (LH) pulses using female goats. Nalfurafine (0, 2, 4, 8, or 16 μg/head) was intravenously injected into ovariectomized Shiba goats. The multiple unit activity (MUA) in the ARC area was recorded, and plasma LH concentrations were measured 2 and 48 h before and after injection, respectively. The MUA volley interval during 0-2 h after injection was significantly increased in the nalfurafine 8 and 16 μg groups compared with the vehicle group. In 0-2 h after injection, the number of LH pulses was significantly decreased in the nalfurafine 8 and 16 μg groups, and the mean and baseline LH were significantly decreased in all nalfurafine-treated groups (2, 4, 8, and 16 μg) compared with the vehicle group. These results suggest that nalfurafine inhibits the activity of the GnRH pulse generator in the ARC, thus suppressing pulsatile LH secretion. Therefore, nalfurafine could be used as a reproductive inhibitor in mammals.
表达 kisspeptin、神经激肽 B 和强啡肽 A（KNDy 神经元）的神经元位于下丘脑弓状核（ARC），被认为是促性腺激素释放激素（GnRH）脉冲发生器。强啡肽 A 据报道可抑制 GnRH 脉冲发生器活性。那拉曲坦是κ-阿片受体（KOR）的选择性激动剂，是强啡肽 A 的受体，临床上用作止痒药。本研究旨在评估那拉曲坦对 GnRH 脉冲发生器活性和黄体生成素（LH）脉冲的影响，使用雌性山羊进行实验。将那拉曲坦（0、2、4、8 或 16μg/只）静脉注射到卵巢切除的 Shiba 山羊体内。记录 ARC 区域的多单位活动（MUA），并分别在注射前 2 小时和注射后 48 小时测量血浆 LH 浓度。与载体组相比，注射后 0-2 小时内，那拉曲坦 8μg 和 16μg 组的 MUA 爆发间隔明显增加。在注射后 0-2 小时内，那拉曲坦 8μg 和 16μg 组的 LH 脉冲数明显减少，所有那拉曲坦处理组（2、4、8 和 16μg）的平均和基础 LH 均明显低于载体组。这些结果表明，那拉曲坦抑制 ARC 中 GnRH 脉冲发生器的活性，从而抑制 LH 脉冲分泌。因此，那拉曲坦可作为哺乳动物的生殖抑制剂。
