Chronic Peripheral Administration of Kappa-Opioid Receptor Antagonist Advances Puberty Onset Associated with Acceleration of Pulsatile Luteinizing Hormone Secretion in Female Rats

Abstract

Puberty in mammals is timed by an increase in gonadotropin-releasing hormone (GnRH) secretion. Previous studies have shown involvement of the two neuropeptides, kisspeptin and neurokinin B (NKB), in controlling puberty onset. Little is known about the role of the other key neuropeptide, dynorphin, in controlling puberty onset, although these three neuropeptides colocalize in the arcuate kisspeptin neurons. The arcuate kisspeptin neuron, which is also referred to as the KNDy neuron, has recently been considered to play a role as an intrinsic source of the GnRH pulse generator. The present study aimed to determine if attenuation of inhibitory dynorphin-kappa-opioid receptor (KOR) signaling triggers the initiation of puberty in normal developing female rats. The present study also determined if stimulatory NKB-neurokinin 3 receptor (NK3R) signaling advances puberty onset. Female Wistar-Imamichi rats were weaned and intraperitoneally implanted with osmotic minipumps filled with nor-binaltorphimine (nor-BNI), a KOR antagonist, or senktide, a NK3R agonist, at 20 days of age. Fourteen days of intraperitoneal infusion of nor-BNI or senktide advanced puberty onset, manifested as vaginal opening and the first vaginal estrus in female rats. Frequent blood sampling showed that nor-BNI significantly increased luteinizing hormone (LH) pulse frequency at 29 days of age compared with vehicle-treated controls. Senktide tended to increase this frequency, but its effect was not statistically significant. The present results suggest that the inhibitory input of dynorphin-KOR signaling plays a role in the prepubertal restraint of GnRH/LH secretion in normal developing female rats and that attenuation of dynorphin-KOR signaling and increase in NKB-NK3R signaling trigger the onset of puberty in female rats.

Neurokinin B receptor agonist and Dynorphin receptor antagonist stimulated luteinizing hormone secretion in fasted male rodents

“…In addition, KOR antagonist advanced pulsatile LH secretion in prepubertal female rats [23]. Furthermore, central nor-BNI administration significantly increased LH secretion in OVX with E 2 replacement in adult female rats [13].…”

“…NKB also stimulated multiple-unit electrical activity (MUA) volleys in ARC as well as LH secretion in OVX goat [9]. In addition, chronic peripheral administration of senktide increases pulsatile LH secretion and advanced puberty onset in female rat [23]. Furthermore, repeated central administration of senktide advanced puberty onset that was suppressed by negative energy balance in female rats [24].…”

Efeito da dieta hiperlipídica sobre a responsividade de neurônios kisspeptidérgicos à leptina

“…A importância da NKB e da DYN na progressão da puberdade e no controle da secreção pulsátil de GnRH e LH, é demonstrada por trabalhos utilizando antagonistas e agonistas de seus receptores de membrana, NK3R e KOR, respectivamente LI et al, 2014;MOSTARI et al, 2013;NAKAHARA et al, 2013;NAVARRO et al, 2012;WAKABAYASHI et al, 2010). A injeção intracerebroventricular do agonista de NK3R, senktide, induz aumento dos níveis de LH, tanto em fêmeas pré-púberes NAVARRO et al, 2012) como em fêmeas adultas, no diestro .…”

“…Esse efeito esteve associado com a antecipação da secreção pulsátil de LH em ratas pré-púberes induzida tanto pelo antagonista de KOR como pelo o agonista de NK3R, sendo que o antagonista de KOR promoveu significativo aumento da frenquência de pulso de LH nessa fase. Dessa forma, Nakahara et al, (2013) sugere que a sinalização da DYN-KOR pode estar relacionada à inibição da secreção de GnRH e LH no período pré-púbere, ao passo que, a sinalização da NKB-NK3R pode estimular a secreção pulsátil de GnRH e LH durante o início da puberdade (NAKAHARA et al, 2013). Apesar deste trabalho não avaliar o sítio de antagonismo do receptor KOR e de agonismo do receptor NKR3, os autores sugerem que a sinalização de DYN-KOR e NKB-NK3R em neurônios KNDy no ARC podem modular a secreção pulsátil de kisspeptina, que por sua vez atua em neurônios GnRHérgicos, promovendo a secreção pulsátil de GnRH.…”

“…de senktide estimula a secreção pulsátil de LH NAKAHARA et al, 2013), ao passo que em animais ovariectomizados a administração icv. de senktide promove inibição da secreção pulsátil de LH NAVARRO et al, 2009NAVARRO et al, , 2011aSANDOVAL-GUZMÁN;RANCE, 2004).…”