UMR 7247, Physiologie de la Reproduction et des Comportements (INRA/CNRS/Université Tours/Haras Nationaux), 37380 Nouzilly, France.
J Neuroendocrinol. 2012 May;24(5):725-36. doi: 10.1111/j.1365-2826.2012.02283.x.
GPR147 and its endogenous ligands, RFRPs, are emerging as important actors in hypothalamic-pituitary axis control. The role of this system would be to inhibit gonadotrophin secretion. However, data on the subject are contradictory. The discovery of RF9 (adamantanecarbonyl-RF-2-NH(2)), a GPR147 antagonist, prompted us to use this new tool to further investigate this system in the ewe. Accordingly, we tested the effect of i.c.v. administration of RF9 on gonadotrophin secretion in the ewe during anoestrous and the breeding season. Intracerebroventricular injections of RF9 (from 50-450 nmol) caused a clear elevation in peripheral blood plasma luteinising hormone (LH) concentrations. The effect of RF9 on LH was more pronounced during the anoestrous season. Furthermore, peripheral administration of RF9 as a bolus (2.1, 6.2 and 12.4 μmol per ewe) or as a constant i.v. infusion (2.1, 6.2, 12.4 and 18.6 μmol/h per ewe) to anoestrous acyclic ewes induced a sustained increase in LH plasma concentrations. A pharmacokinetic study showed that RF9 (12.4 μmol bolus i.v.) has an effective half life of 5.5 h in the plasma. Conversely, RF9 is not detectable in the cerebrospinal fluid, suggesting that it does not cross the blood-brain barrier. The increase in LH plasma concentrations induced by RF9 was blocked by previous administration of 1.3 μmol per ewe of gondotrophin-releasing hormone (GnRH) antagonist Teverelix. This suggests that GnRH is involved in the stimulatory effect of RF9 on gonadotrophin secretion. Finally, no variation in LH plasma concentrations could be detected in ovariectomised ewes injected either i.c.v. or i.v. with RFRP3 (VPNLPQRF-NH(2)). The lack of effect of RFRP3 in our experimental setting suggests that the mechanisms involved in RF9 action are probably more complex than previously assumed. Our results indicate that delivery of RF9 in the ewe greatly increases gondadotrophin secretion in both the oestrus and anoestrus season, suggesting a potential new way of controlling reproduction in mammals.
GPR147 及其内源性配体 RFRP 作为下丘脑-垂体轴控制的重要因素正在出现。该系统的作用将是抑制促性腺激素的分泌。然而，关于该主题的数据存在矛盾。RF9（金刚烷甲酰基-RF-2-NH2）的发现，一种 GPR147 拮抗剂，促使我们使用这种新工具在绵羊中进一步研究该系统。因此，我们测试了侧脑室给予 RF9 对非发情期和繁殖季节绵羊促性腺激素分泌的影响。侧脑室注射 RF9（50-450nmol）导致外周血血浆黄体生成素（LH）浓度明显升高。RF9 对 LH 的作用在非发情期更为明显。此外，外周给予 RF9 作为单次推注（每只羊 2.1、6.2 和 12.4μmol）或作为持续静脉输注（每只羊 2.1、6.2、12.4 和 18.6μmol/h）给非发情的非周期性绵羊，可诱导 LH 血浆浓度持续升高。药代动力学研究表明，RF9（12.4μmol 静脉内推注）在血浆中的有效半衰期为 5.5 小时。相反，RF9 在脑脊液中无法检测到，表明它不能穿过血脑屏障。RF9 引起的 LH 血浆浓度升高被先前给予每只羊 1.3μmol 的促性腺激素释放激素（GnRH）拮抗剂 Teverelix 阻断。这表明 GnRH 参与了 RF9 对促性腺激素分泌的刺激作用。最后，在注射了 RFRP3（VPNLPQRF-NH2）的卵巢切除绵羊中，无论是侧脑室还是静脉内注射，LH 血浆浓度均未发生变化。在我们的实验设置中，RFRP3 没有作用表明 RF9 作用的机制可能比以前假设的更为复杂。我们的结果表明，在绵羊中给予 RF9 可大大增加发情和非发情季节的促性腺激素分泌，这表明控制哺乳动物生殖的一种新方法。
