Li Xiao Feng, Bowe James E, Mitchell Jacqueline C, Brain Susan D, Lightman Stafford L, O'Byrne Kevin T
Centre for Reproduction, Endocrinology and Diabetes, New Hunt's House, King's College London, Guy's Campus, United Kingdom.
Endocrinology. 2004 Apr;145(4):1556-63. doi: 10.1210/en.2003-1609. Epub 2004 Jan 21.
In addition to its role as a potent vasodilator, calcitonin gene-related peptide (CGRP) is centrally involved in a variety of stress responses, including activation of the hypothalamo-pituitary-adrenocortical axis. It is well known that stress suppresses the activity of the hypothalamic GnRH pulse generator, the central regulator of LH and FSH pulses, resulting in reproductive dysfunction. The aim of this study was to test the hypothesis that CGRP has a critical role in mediating stress-induced suppression of pulsatile LH secretion in the rat. Ovariectomized rats were implanted with intracerebroventricular and iv cannulae. Central administration of CGRP (75 pmol-1.2 nmol) into the lateral cerebral ventricle resulted in a profound, dose-dependent suppression of LH pulses, which was reversed by a CGRP receptor antagonist (CGRP(8-37),1 nmol). Although the site of action of CGRP remains to be established, the induction of c-Fos expression in the preoptic area and hypothalamic paraventricular nucleus might suggest an involvement of these brain regions. Intravenous administration of CGRP did not affect LH pulses. Coadministration (intracerebroventricular) of CGRP (400 pmol) with a CRH antagonist (alpha-helical CRF(9-41), 26 nmol) partly blocked the CGRP-induced suppression of LH pulses. Furthermore, CGRP(8-37) (1 nmol) completely blocked hypoglycemic stress-induced suppression of LH pulses. These results suggest that the suppression of pulsatile LH secretion by central administration of CGRP may be mediated in part by CRH, and that CGRP may play a pivotal role in the normal physiological response of stress-induced suppression of the hypothalamic GnRH pulse generator, and hence the reproductive system.
除了作为一种强效血管舒张剂发挥作用外，降钙素基因相关肽（CGRP）还在多种应激反应中起核心作用，包括下丘脑-垂体-肾上腺皮质轴的激活。众所周知，应激会抑制下丘脑促性腺激素释放激素（GnRH）脉冲发生器的活性，而GnRH脉冲发生器是促黄体生成素（LH）和促卵泡生成素（FSH）脉冲的中枢调节因子，从而导致生殖功能障碍。本研究的目的是验证以下假说：CGRP在介导应激诱导的大鼠LH脉冲分泌抑制中起关键作用。对去卵巢大鼠植入脑室内和静脉内插管。向大脑侧脑室中央注射CGRP（75 pmol - 1.2 nmol）会导致LH脉冲出现显著的、剂量依赖性抑制，这种抑制可被CGRP受体拮抗剂（CGRP(8 - 37)，1 nmol）逆转。尽管CGRP的作用位点尚待确定，但视前区和下丘脑室旁核中c-Fos表达的诱导可能提示这些脑区参与其中。静脉注射CGRP不影响LH脉冲。将CGRP（400 pmol）与促肾上腺皮质激素释放激素（CRH）拮抗剂（α-螺旋CRF(9 - 41)，26 nmol）联合（脑室内）给药可部分阻断CGRP诱导的LH脉冲抑制。此外，CGRP(8 - 37)（1 nmol）可完全阻断低血糖应激诱导的LH脉冲抑制。这些结果表明，通过中央给药CGRP抑制LH脉冲分泌可能部分由CRH介导，并且CGRP可能在应激诱导下丘脑GnRH脉冲发生器抑制进而影响生殖系统的正常生理反应中起关键作用。
