Neurokinin B Acts via the Neurokinin-3 Receptor in the Retrochiasmatic Area to Stimulate Luteinizing Hormone Secretion in Sheep

Abstract

Recent data have demonstrated that mutations in the receptor for neurokinin B (NKB), the NK-3 receptor (NK3R), produce hypogonadotropic hypogonadism in humans. These data, together with reports that NKB expression increases after ovariectomy and in postmenopausal women, have led to the hypothesis that this tachykinin is an important stimulator of GnRH secretion. However, the NK3R agonist, senktide, inhibited LH secretion in rats and mice. In this study, we report that senktide stimulates LH secretion in ewes. A dramatic increase in LH concentrations to levels close to those observed during the preovulatory LH surge was observed after injection of 1 nmol senktide into the third ventricle during the follicular, but not in the luteal, phase. Similar increases in LH secretion occurred after insertion of microimplants containing this agonist into the retrochiasmatic area (RCh) in anestrous or follicular phase ewes. A low-dose microinjection (3 pmol) of senktide into the RCh produced a smaller but significant increase in LH concentrations in anestrous ewes. Moreover, NK3R immunoreactivity was clearly evident in the RCh, although it was not found in A15 dopaminergic cell bodies in this region. These data provide evidence that NKB stimulates LH (and presumably GnRH) secretion in ewes and point to the RCh as one important site of action. Based on these data, and the effects of NK3R mutations in humans, we hypothesize that NKB plays an important stimulatory role in the control of GnRH and LH secretion in nonrodent species.

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

“…Instead the reader is referred to a recent comprehensive review 129 . Other studies in monkeys 130 , goats 131 and sheep 132 show a clear stimulatory role for NKB in gonadotropin secretion; in keeping with the observations in humans of decreased LH in the absence of NKB signaling. The patients with inactivating mutations of genes encoding NKB or its receptor were characterized by very low LH but normal or near-normal circulating FSH levels 9 .…”

“…Since GnRH neurons express GPR54 but apparently not TACR3 132,137,138 , while KNDY do express TACR3, it was further postulated that NKB secreted from KNDY neurons acts in an autocrine or paracrine manner to enhance KP secretion and that NKB actions were upstream of KP 134 . This notion was supported by the demonstration that continuous infusion of KP at a GPR54-saturating concentration in patients with NKB and TACR3 inactivating mutations restored LH pulsatility 134 .…”

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“…In this context, proof of desensitization of NKB-induced LH responses has been presented in the monkey (28). This desensitization might account for the null or even inhibitory effect of senktide on LH secretion in GNX rodents and ewes (25,33,34,37), as they are expected to have pre-elevated, endogenous levels of NKB. Anyhow, the hypogonadotropic phenotype of humans with inactivating mutations of the NKB pathway, together with the reported effects of NKB agonists on LH release under physiological conditions in different species, solidly document the predominant stimulatory role of NKB in the central control of the HPG axis.…”

“…In keeping with the hypogonadotropic phenotype of patients with inactivating mutations of the NKB system, a number of studies in ewes, monkeys, mice, and rats have documented stimulatory actions of the NKB agonist, senktide, on LH secretion (28,33,34,35). Of note, the stimulatory effects of senktide on LH secretion were abrogated in Gpr54 null mice, thus suggesting that these require the integrity of kisspeptin signaling to manifest (35), a contention that is also supported by recent findings in the monkey (36).…”

Prenatal androgen excess enhances stimulation of the GNRH pulse in pubertal female rats

“…However, the effects of NKB on the regulation of GNRH/LH secretion remain controversial in humans and animal models. In the ewe, activation of NK3R with senktide, a potent and selective NK3R agonist, consistently stimulates LH secretion (Billings et al 2010). In contrast to humans and sheep, senktide suppressed LH secretion in rats (Sandoval-Guzman & Rance 2004) and mice (Castellano et al 2009).…”