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

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.