Neurokinin B and the hypothalamic regulation of reproduction

Abstract

The morphology and gene expression of neurokinin B (NKB) neurons is altered in the human infundibular (arcuate) nucleus in association with the ovarian failure of menopause. Also, gonadotropin releasing-hormone (GnRH) mRNA is elevated and proopiomelanocortin (POMC) mRNA decreased. To determine if loss of ovarian steroids could produce comparable changes in gene expression in primates, we measured the effects of ovariectomy on NKB and GnRH in young cynomolgus monkeys. We also measured POMC gene expression, serum leptin and body weight to examine the consequences of ovariectomy on energy balance. Neurokinin B neurons in the infundibular nucleus of ovariectomized monkeys were larger, more numerous and displayed increased levels of NKB mRNA than the intact controls. Ovariectomy increased the number of neurons expressing GnRH gene transcripts. In contrast, the energy balance parameters were unchanged by ovariectomy. This study provides strong support for the hypothesis that ovarian failure contributes to the morphological changes and increased NKB and GnRH gene expression observed in postmenopausal women. We hypothesized that hypothalamic NKB neurons participate in the hypothalamic circuitry regulating LH. We determined if intracerebral infusion of a NK 3 receptor agonist alters serum LH in the ovariectomized estrogen-treated rat. A significant inhibition of serum LH was observed after senktide injection, accompanied by changes in Fos expression in medial preoptic area, arcuate, paraventricular and supraoptic nuclei. This study provides evidence that stimulation of the NK3 receptor may inhibit LH secretion via activation of hypothalamic neurons. To further investigate the role of NKB in gonadotropin regulation, we infused an antisense oligodeoxynucleotide targeted to the NKB gene in gonadectomized rats. In support of our hypothesis, the downregulation of NKB decreased serum LH by 25%. To analize the participation of the NKB receptor, NK3, we targeted an antisense to the receptor. Rats injected with the NK3 antisense exhibited no change in serum LH. Furthermore, injection of SB-222200, a NK3 antagonist, did not modify serum LH. These data suggest that NKB may regulate gonadotropin secretion through more than one receptor. Taken together, these studies provide some of the first detailed information on the relationship between NKB neurons, and the reproductive axis.