Walsh J P, Clarke I J
Prince Henry's Institute of Medical Research, Clayton, Vic., Australia.
Neuroendocrinology. 1998 Mar;67(3):164-70. doi: 10.1159/000054311.
Endogenous opioid systems in the hypothalamus inhibit gonadotropin-releasing hormone (GnRH) secretion, and a reduction in this inhibitory input (disinhibition) is thought to be part of the neural mechanism of the preovulatory GnRH/luteinizing hormone (LH) surge. We showed previously that intracerebroventricular infusion of the highly specific opioid mu-receptor agonist DAMGO delayed the oestrogen-induced LH surge in ovariectomized (OVX) ewes, whereas both delta- and kappa-agonists were ineffective. The aim of the present study was to establish the anatomical site of this effect. The most likely hypothalamic sites of action are the medial preoptic area (MPOA), where most GnRH perikarya are located in sheep, and/or the median eminence (ME), where GnRH fibres terminate on hypophysial portal blood vessels. Conscious, unrestrained OVX ewes with permanent bilateral guide tubes implanted into either the MPOA or the mediobasal hypothalamus (MBH), close to the ME, were injected (i.m.) with oestradiol benzoate (EB) 50 microg (t = 0 h). In this model, EB elicits a time-delayed surge in LH secretion after 13-19 h. Jugular venous blood was sampled at half-hourly intervals from -2 to 0 h, and from 10 to 26 h. From 12 to 20 h, bilateral infusions of either the highly specific opioid mu-agonist DAMGO (40 nmol/h bilaterally) or saline were given into the MPOA or MBH at 2.5 microl/h. Guide tube placements were confirmed histologically. The mean (+/- SEM) time to the onset of the LH surge was significantly (p < 0.01) increased in the animals (n = 9) that received DAMGO infusion into the MPOA (20.5 +/- 1.4 vs. 15.7 +/- 0.6 h in the saline-infused controls). The effect was clearly apparent in 6/9 of the DAMGO-infused animals. The mean (+/- SEM) time to LH surge onset was also significantly (p < 0.01) increased in the animals (n = 8) that received DAMGO infusion into the MBH (19.7 +/- 1.2 vs. 14.3 +/- 0.5 h). In this case, the effect was clearly apparent in 4/8 of the DAMGO-infused animals. We conclude that bilateral infusion of DAMGO into either the MPOA or the MBH can delay the EB-induced LH surge in OVX ewes. These data provide further evidence for dual hypothalamic sites of opioid regulation of GnRH secretion, and are consistent with the hypothesis that disinhibition from opioid tone at both the MPOA and MBH/ME is permissive of the preovulatory GnRH/LH surge.
下丘脑内的内源性阿片系统会抑制促性腺激素释放激素（GnRH）的分泌，而这种抑制性输入的减少（去抑制作用）被认为是排卵前GnRH/黄体生成素（LH）激增的神经机制的一部分。我们之前表明，向脑室注射高特异性阿片μ受体激动剂DAMGO会延迟雌激素诱导的去卵巢（OVX）母羊的LH激增，而δ和κ激动剂则无效。本研究的目的是确定这种作用的解剖部位。最可能的下丘脑作用部位是内侧视前区（MPOA），绵羊的大多数GnRH神经元胞体位于此处，和/或正中隆起（ME），GnRH纤维在此处终止于垂体门脉血管。将双侧永久性引导管植入到MPOA或靠近ME的下丘脑中间基底部（MBH）的清醒、未受约束的OVX母羊，肌肉注射50微克苯甲酸雌二醇（EB）（t = 0小时）。在这个模型中，EB在13 - 19小时后引发LH分泌的延迟激增。在-2至0小时以及10至26小时期间，每隔半小时采集颈静脉血样。在12至20小时期间，以2.5微升/小时的速度将高特异性阿片μ激动剂DAMGO（40纳摩尔/小时，双侧）或生理盐水双侧注入MPOA或MBH。通过组织学确认引导管的位置。在向MPOA注入DAMGO的动物（n = 9）中，LH激增开始的平均（±SEM）时间显著增加（p < 0.01）（分别为20.5 ± 1.4小时和生理盐水注入对照组的15.7 ± 0.6小时）。在6/9注入DAMGO的动物中，这种效应明显。在向MBH注入DAMGO的动物（n = 8）中，LH激增开始的平均（±SEM）时间也显著增加（p < 0.01）（分别为19.7 ± 1.2小时和14.3 ± 0.5小时）。在这种情况下，在4/8注入DAMGO的动物中，这种效应明显。我们得出结论，向MPOA或MBH双侧注入DAMGO可延迟EB诱导的OVX母羊的LH激增。这些数据为阿片类物质对GnRH分泌调节的双下丘脑部位提供了进一步的证据，并且与以下假设一致：MPOA和MBH/ME处阿片类物质张力的去抑制作用允许排卵前GnRH/LH激增。
