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Stimulatory effect of a specific substance P antagonist (RPR 100893) of the human NK 1 receptor on the estradiol‐induced LH and FSH surges in the ovariectomized cynomolgus monkey
Author(s) -
Kerdelhué Bernard,
Gordon Keith,
Williams Robert,
Lenoir Véronique,
Fardin Valérie,
Chevalier Paul,
Garret Claude,
Duval Pierre,
Kolm Paul,
Hodgen Gary,
Jones Howard,
Jones Georgeanna Segard
Publication year - 1997
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/(sici)1097-4547(19971001)50:1<94::aid-jnr10>3.0.co;2-a
Subject(s) - ovariectomized rat , endocrinology , medicine , antagonist , luteinizing hormone , receptor antagonist , receptor , follicle stimulating hormone , estradiol benzoate , hormone , chemistry , pharmacology , biology
Utilizing a human NK 1 receptor antagonist (RPR 100893), the present in vivo study was designed to test the hypothesis that endogenous substance P (SP) modulates the action of 17β‐estradiol in inducing luteinizing hormone (LH) and follicle stimulating hormone (FSH) surges in ovariectomized cynomolgus monkey. Plasma concentrations of LH and FSH as well as NK 1 receptor antagonist and SP were measured during the development of the negative and positive feedback phases which follow a single administration of estradiol benzoate (50 μg/kg) to long‐term ovariectomized monkeys. Daily administration by gastric intubation of 1 mg/kg or 10 mg/kg of the NK 1 receptor antagonist (RPR 100893) leads to detectable levels of the antagonist in the blood of treated animals for at least 6 hr after its administration. These levels are in agreement with the experimentally determined IC 50 value of the antagonist. The most striking finding of this study is that LH and FSH releases are enhanced during the descending arm of the estradiol benzoate‐induced LH and FSH surges, which suggests that endogenous SP normally has an inhibitory role during this time. The enhancement of LH release is approximately 50%, regardless of the amount of the NK 1 antagonist used. However, the enhanced FSH release is more important. Furthermore, blockade of the NK 1 receptor with the smaller dose of the antagonist leads to a small, but significant, increase in plasma levels of SP, indicating that blockade of SP receptors leads to an increased release of SP. Collectively, these results further substantiate the link which exists between the ovarian steroid 17β‐estradiol and SP systems. Also, for the first time, these results demonstrate an inhibitory involvement of the human NK 1 receptor in the 17β‐estradiol‐induced pseudo‐ovulatory gonadotropin surges in the ovariectomized monkey. J. Neurosci. Res. 50:94–103, 1997. © 1997 Wiley‐Liss, Inc.