Ebling F J, Schwartz M L, Foster D L
Reproductive Sciences Program, University of Michigan, Ann Arbor 48109.
Endocrinology. 1989 Jul;125(1):369-83. doi: 10.1210/endo-125-1-369.
The developing female sheep, which attains puberty after 25 weeks of age, was used as an experimental model to investigate the role of endogenous opioid peptides in the control of pulsatile LH secretion during sexual maturation. Treatment of ovary-intact prepubertal sheep at 12 weeks of age with the opiate antagonist naloxone resulted in a dose-dependent increase in LH secretion. Subsequent studies used ovariectomized (OVX) lambs implanted with capsules containing 17 beta-estradiol to provide a constant, ovarian steroid feedback signal throughout development. Naloxone treatment (hourly iv injections of 1 mg/kg BW for 4 h) produced an increase in the frequency of episodic LH secretion at all prepubertal ages, when lambs were highly sensitive to the estradiol negative feedback. However, increases in LH pulse frequency were also induced by naloxone treatment at a postpubertal age in estradiol-treated OVX sheep, indicating that opioid inhibition is still present at a time when sensitivity to the feedback effects of ovarian steroids is markedly reduced and endogenous LH secretion is increased. These observations in ovary-intact and estradiol-treated OVX lambs suggest that opioid mechanisms inhibit pulsatile tonic LH secretion during both the prepubertal and postpubertal periods. Endogenous opioid inhibition of LH secretion is not dependent on the presence of ovarian steroids, as evidenced by the response to naloxone 3 weeks after removal of an estradiol implant from OVX lambs, when LH pulse frequency was already high. Naloxone treatment increased LH pulse frequency further, at both a prepubertal age (18 weeks) and a postpubertal age (38 weeks). Naloxone also increased LH pulse frequency in OVX lambs in which LH secretion was inhibited chronically by progesterone rather than by estradiol. The response to naloxone was similar in postpubertal P-treated OVX lambs and age-matched prepubertal P-treated OVX controls in which puberty had been delayed by means of an inhibitory seasonal photoperiod. In addition, after removal of steroid implants to allow LH secretion to increase, the degree of inhibition of LH secretion by the opiate agonist morphine was similar between age-matched postpubertal sheep and those with photoperiodically delayed puberty. We conclude that endogenous opioid mechanisms are an important inhibitory mechanism controlling pulsatile LH secretion in the developing sheep. However, changes in opioid inhibition are unlikely to underlie the decrease in sensitivity to steroid negative feedback and increase in pulsatile LH secretion that occur at puberty.
发育中的雌性绵羊在25周龄后达到青春期，被用作实验模型，以研究内源性阿片肽在性成熟过程中对促黄体生成素（LH）脉冲式分泌控制中的作用。对12周龄的未成熟完整卵巢绵羊用阿片拮抗剂纳洛酮进行处理，导致LH分泌呈剂量依赖性增加。随后的研究使用植入含17β-雌二醇胶囊的去卵巢（OVX）羔羊，以便在整个发育过程中提供持续的卵巢类固醇反馈信号。纳洛酮处理（每小时静脉注射1mg/kg体重，共4小时）在所有未成熟年龄均使LH脉冲式分泌频率增加，此时羔羊对雌二醇负反馈高度敏感。然而，在青春期后年龄，对接受雌二醇处理的OVX绵羊进行纳洛酮处理也诱导了LH脉冲频率增加，这表明在对卵巢类固醇反馈作用的敏感性显著降低且内源性LH分泌增加时，阿片类物质的抑制作用仍然存在。在完整卵巢和接受雌二醇处理的OVX羔羊中的这些观察结果表明，阿片类机制在青春期前和青春期后均抑制LH的脉冲式基础分泌。内源性阿片类物质对LH分泌的抑制不依赖于卵巢类固醇的存在，从OVX羔羊中取出雌二醇植入物3周后对纳洛酮的反应就证明了这一点，此时LH脉冲频率已经很高。纳洛酮处理在青春期前年龄（18周）和青春期后年龄（38周）均进一步增加了LH脉冲频率。纳洛酮也使LH分泌被孕酮而非雌二醇长期抑制的OVX羔羊的LH脉冲频率增加。在青春期后接受孕酮处理的OVX羔羊和通过抑制性季节性光周期使青春期延迟的年龄匹配的青春期前接受孕酮处理的OVX对照中，对纳洛酮的反应相似。此外，在取出类固醇植入物以使LH分泌增加后，阿片激动剂吗啡对LH分泌的抑制程度在年龄匹配的青春期后绵羊和光周期延迟青春期的绵羊之间相似。我们得出结论，内源性阿片类机制是控制发育中绵羊LH脉冲式分泌的重要抑制机制。然而，阿片类抑制作用的变化不太可能是青春期时对类固醇负反馈敏感性降低和LH脉冲式分泌增加的基础。
