Stimulatory effect of a specific substance P antagonist (RPR 100893) of the human NK1 receptor on the estradiol-induced LH and FSH surges in the ovariectomized cynomolgus monkey

Bernard Kerdelhué, Keith Gordon, Robert Williams, Véronique Lenoir, Valérie Fardin, Paul Chevalier, Claude Garret, Pierre Duval, Paul Kolm, Gary Hodgen, Howard Jones, Georgeanna Segard Jones

Research output: Contribution to journalArticle

Abstract

Utilizing a human NK1 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 NK1 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 NK1 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 IC50 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 NK1 antagonist used. However, the enhanced FSH release is more important. Furthermore, blockade of the NK1 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 NK1 receptor in the 17β-estradiol- induced pseudo-ovulatory gonadotropin surges in the ovariectomized monkey.

Original languageEnglish (US)
Pages (from-to)94-103
Number of pages10
JournalJournal of Neuroscience Research
Volume50
Issue number1
DOIs
StatePublished - Oct 1 1997
Externally publishedYes

Fingerprint

Estradiol Receptors
Macaca fascicularis
Follicle Stimulating Hormone
Substance P
Luteinizing Hormone
Estradiol
Haplorhini
Neurokinin-1 Receptor Antagonists
Neurokinin-1 Receptors
Gonadotropins
Intubation
Inhibitory Concentration 50
Stomach
Steroids
RPR 100893

Keywords

  • Estradiol
  • FSH
  • LH
  • Monkey
  • NK receptor

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Stimulatory effect of a specific substance P antagonist (RPR 100893) of the human NK1 receptor on the estradiol-induced LH and FSH surges in the ovariectomized cynomolgus monkey. / 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.

In: Journal of Neuroscience Research, Vol. 50, No. 1, 01.10.1997, p. 94-103.

Research output: Contribution to journalArticle

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. / Stimulatory effect of a specific substance P antagonist (RPR 100893) of the human NK1 receptor on the estradiol-induced LH and FSH surges in the ovariectomized cynomolgus monkey. In: Journal of Neuroscience Research. 1997 ; Vol. 50, No. 1. pp. 94-103.
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abstract = "Utilizing a human NK1 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 NK1 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 NK1 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 IC50 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 NK1 antagonist used. However, the enhanced FSH release is more important. Furthermore, blockade of the NK1 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 NK1 receptor in the 17β-estradiol- induced pseudo-ovulatory gonadotropin surges in the ovariectomized monkey.",
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AU - Gordon, Keith

AU - Williams, Robert

AU - Lenoir, Véronique

AU - Fardin, Valérie

AU - Chevalier, Paul

AU - Garret, Claude

AU - Duval, Pierre

AU - Kolm, Paul

AU - Hodgen, Gary

AU - Jones, Howard

AU - Jones, Georgeanna Segard

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N2 - Utilizing a human NK1 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 NK1 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 NK1 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 IC50 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 NK1 antagonist used. However, the enhanced FSH release is more important. Furthermore, blockade of the NK1 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 NK1 receptor in the 17β-estradiol- induced pseudo-ovulatory gonadotropin surges in the ovariectomized monkey.

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