Involvement of Neurokinin Receptors in the Control of Pulsatile Luteinizing Hormone Secretion in Rats

Abstract

Abstract. It has recently been shown that neurokinin B, a tachykinin, is associated with GnRH pulse generation in sheep and goats. The aim of the present study was to clarify the role of tachykinin receptors in the control of LH secretion in rats. To this end, we evaluated the effect of CS-003, an antagonist for all three neurokinin receptors (NK1, NK2 and NK3 receptors), on pulsatile LH secretion in both sexes of rats with different routes of administration. Both oral and third ventricular administration of CS-003 suppressed LH secretion in both sexes of gonadectomized animals. Furthermore, intact male rats with oral administration of CS-003 showed decreased serum testosterone levels, which might be due to suppressed LH secretion. None of the three subtype-specific neurokinin receptor antagonists showed a significant effect on LH secretion in ovariectomized rats when each antagonist was singly administered. The present results suggest that neurokinins play a role in the control of pulsatile GnRH/LH secretion via multiple neurokinin receptors in both male and female rats. Key words: Luteinizing hormone, Neurokinin, Rat, Receptor (J. Reprod. Dev. 57: [409][410][411][412][413][414][415] 2011) ulsatile gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) release is indispensable for regulation of gonadal functions, such as folliculogenesis, spermatogenesis and steroidogenesis, in rodents [1], ruminants [2,3] and primates [4]. The mechanism generating GnRH/LH pulses, called the GnRH pulse generator, has been suggested to be localized in the hypothalamus [5]. Recent studies have revealed that kisspeptin neurons located in the hypothalamus play a central role in regulating GnRH release [6,7]. Kisspeptin neurons have two populations in the hypothalamus [8]: One is located in the hypothalamic arcuate nucleus (ARC), and the other is located in the anteroventral periventricular nucleus (AVPV). Of these two populations, the AVPV kisspeptin neurons have been reported to be involved in the regulation of GnRH/LH surge [9,10]. On the other hand, the role of ARC kisspeptin neurons is still unclear, but several lines of evidence suggest that the population is associated with GnRH pulse generation [11].Recent studies have shown an interesting and essential aspect of the ARC kisspeptin neurons. Most kisspeptin neurons have neurokinin B (NKB) and dynorphin (Dyn) in sheep [12], goats [13] and rodents [14], and thus the neurons have been called KNDy neurons [15]. Colocalization of those three neuropeptides in the ARC neurons might be associated with GnRH pulse generation. It has recently been reported that mutations of genes encoding NKB and its receptor are associated with gonadotropin deficiency in humans [16], and central administration of a selective NKB receptor agonist stimulates LH secretion in sheep [17] and monkeys [18]. These reports indicate the significance of NKB/NK3 signaling in GnRH/gonadotropin release in these animal species. In addition to neurokinin B, nor-BNI, a κ-opioid receptor antagonist (KOR), rev...

Expanding the role of tachykinins in the neuroendocrine control of reproduction

“…Of note, this study showed that, in vitro, the activation of kisspeptin neurons by NKB was completely diminished only when all three neurokinin receptor (NKR) subtypeselective antagonists were concomitantly applied in the in vitro bath (de Croft et al 2013). This is in line with studies carried out in vivo indicating that blockade of all 3 tachykinin receptors (but not each one of them individually) prevented the compensatory rise of LH after gonadectomy (GDX) in rats (Noritake et al 2011). Therefore, considerable cross-reactivity exists between these receptor/ligand systems, and each one of these neuropeptides is capable of eliciting responses from all three neurokinin receptors (Cascieri et al 1992, Gether et al 1993, Beaujouan et al 2000.…”

“…Furthermore, KNDy cells are interconnected with NKB fibers within the ARC forming a tightly regulated network (Rance & Bruce 1994, Krajewski et al 2010. Indeed, a growing number of studies in multiple species from our lab and others support the ability of NKB, or the NKB receptor (NK3R) agonist senktide, to increase LH pulses (Grachev et al 2012, Navarro 2013, Goodman et al 2014 (Arisawa et al 1990, Kalra et al 1992, Sahu & Kalra 1992, Noritake et al 2011, de Croft et al 2013 including men (Coiro et al 1992). It is therefore plausible to speculate that these tachykinins are involved in the central regulation of GnRH release and may be additional elements to the GnRH pulse generator.…”

“…These data suggest a likely interaction of NKA with NK1R as well as NK2R, and of NKB with all 3 receptors, at relatively low concentrations. Furthermore, it has been demonstrated in rats that pulsatile LH secretion was suppressed by central administration of CS-003, an antagonist for all three NKRs, whereas administration of each NKR subtypeselective antagonist alone had no effect (Noritake et al 2011). In this respect, several pieces of evidence will be discussed below that provide unequivocal evidence that other members of the tachykinin family, namely SP and NKA, all encoded by the TAC1 or Tac1 gene (Table 1), in humans and rodents respectively (Lasaga & Debeljuk 2011) are an important component of the integrated neuronal hypothalamic system that controls GnRH/LH secretion in mammals.…”

Neurokinin B Activates Arcuate Kisspeptin Neurons Through Multiple Tachykinin Receptors in the Male Mouse

“…This result has interesting parallels with a recent in vivo study in rats where a combined tachykinin receptor antagonist suppressed LH secretion, whereas individual tachykinin receptor antagonists were ineffective (57). In relation to in vivo studies, it is notable that many investigators have used Senktide to evaluate the effects of the NKB system on gonadotropin control.…”

The Role of Neurokinin B Signalling in Reproductive Neuroendocrinology

“…NKB preferentially binds and activates the neurokin 3 receptor (NK3R), although promiscuous binding to other neurokinin receptor subtypes has been implicated in the modulatory actions of NKB signalling in rodents [40,46]. The initial report of suppressed LH secretion following selective activation of NK3R in OVX + E 2 rats [47] prompted similar experiments in other species.…”