RF9 Powerfully Stimulates Gonadotrophin Secretion in the Ewe: Evidence for a Seasonal Threshold of Sensitivity
RF9 Powerfully Stimulates Gonadotrophin Secretion in the Ewe: Evidence for a Seasonal Threshold of Sensitivity
复制标题
DOI：
10.1111/j.1365-2826.2012.02283.x
复制
发表时间：
2012-05-01
影响因子：
3.2
通讯作者：
Beltramo, M.
中科院分区：
文献类型：
--
作者：
Caraty, A.;Blomenroehr, M.;Beltramo, M.
GPR147及其内源性配体RFRPs在下丘脑-垂体轴控制中发挥着重要作用。这个系统的作用是抑制促性腺激素的分泌。然而，关于这个问题的数据是矛盾的。GPR147拮抗剂RF9 （adamantanecarbonyl-RF-2-NH2）的发现促使我们使用这种新工具进一步研究母羊的这一系统。因此，我们测试了体外注射RF9对母羊发情期和繁殖期促性腺激素分泌的影响。脑室内注射RF9（从50450 nmol开始）导致外周血血浆黄体生成素（LH）浓度明显升高。RF9对LH的影响在发情季节更为明显。此外，外周给药（每只母羊2.1、6.2和12.4 μ mol/h）或持续静脉输注（每只母羊2.1、6.2、12.4和18.6 μ mol/h）的无周期母羊诱导黄体生成素血浆浓度持续升高。一项药代动力学研究表明，RF9 （12.4 μ mol）在血浆中的有效半衰期为5.5 h。相反，脑脊液中检测不到RF9，这表明它不会穿过血脑屏障。每只母羊给予促性腺激素释放激素（GnRH）拮抗剂Teverelix 1.3 μ mol，可阻断RF9诱导的LH血浆浓度升高。这表明GnRH参与了RF9对促性腺激素分泌的刺激作用。最后，在切除卵巢的母羊体内注射RFRP3或静脉注射RFRP3 （VPNLPQRF-NH2）均未检测到LH血浆浓度的变化。在我们的实验环境中，RFRP3缺乏作用，这表明RF9作用的机制可能比之前假设的更复杂。我们的研究结果表明，母羊在发情期和去情期都能显著增加促性腺激素的分泌，这可能是一种控制哺乳动物繁殖的新方法。
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-NH2), 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 50450 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 mu mol per ewe) or as a constant i.v. infusion (2.1, 6.2, 12.4 and 18.6 mu mol/h per ewe) to anoestrous acyclic ewes induced a sustained increase in LH plasma concentrations. A pharmacokinetic study showed that RF9 (12.4 mu mol 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 bloodbrain barrier. The increase in LH plasma concentrations induced by RF9 was blocked by previous administration of 1.3 mu mol 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-NH2). 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.