RESUMO
Kisspeptin and its receptor GPR54 have been described as key hypothalamic components in the regulation of GnRH secretion. Kisspeptin is also present in several regions of the central nervous system and the peripheral organs and has recently been identified in the superior ganglion. Herein, we tested the possibility that ovarian kisspeptin is regulated by the sympathetic nervous system and participates locally in the regulation of ovarian function. Both ovarian and celiac ganglion kisspeptin mRNA levels increase during development, whereas kisspeptin peptide levels and plasma levels decrease during development. In the celiac ganglion, kisspeptin colocalized with tyrosine hydroxylase, indicating potential kisspeptin synthesis and transport within the sympathetic neurons. A continuous (64 h) cold stress induced marked changes within the kisspeptin neural system along the celiac ganglion-ovary axis. In vitro incubation with the ß-adrenergic agonist isoproterenol increased ovarian kisspeptin mRNA and peptide levels, and this increase was inhibited by treatment with the ß-antagonist propranolol. Sectioning the superior ovarian nerve altered the feedback information within the kisspeptin celiac ganglion-ovary axis. In vivo administration of a kisspeptin antagonist to the left ovarian bursa of 22- to 50-d-old unilaterally ovariectomized rats delayed the vaginal opening, decreased the percentage of estrous cyclicity, and decreased plasma, ovarian, and celiac ganglion kisspeptin concentrations but did not modify the LH plasma levels. These results indicate that the intraovarian kisspeptin system may be regulated by sympathetic nerve activity and that the peptide, either from a neural or ovarian origin, is required for proper coordinated ovarian function.
Assuntos
Ciclo Estral/efeitos dos fármacos , Gânglios Simpáticos/efeitos dos fármacos , Kisspeptinas/antagonistas & inibidores , Rede Nervosa/efeitos dos fármacos , Ovário/inervação , Maturidade Sexual/efeitos dos fármacos , Animais , Ciclo Estral/fisiologia , Feminino , Gânglios Simpáticos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Kisspeptinas/genética , Kisspeptinas/metabolismo , Rede Nervosa/metabolismo , Ovário/efeitos dos fármacos , Ovário/metabolismo , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Maturidade Sexual/fisiologia , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Vagina/metabolismoRESUMO
A substantial fraction of the noradrenergic innervation targeting the mammalian ovary is provided by neurons of the celiac ganglion. Although studies in the rat have shown that noradrenergic nerves reach the ovary near the time of birth, it is unknown how the functional capacity of this innervation unfolds during postnatal ovarian development. To address this issue, we assessed the ability of the developing ovary to incorporate and release (3)H-norepinephrine. Incorporation of (3)H-norepinephrine was low during the first 3 wk of postnatal life, but pharmacological inhibition of norepinephrine (NE) neuronal uptake with cocaine showed that an intact transport mechanism for NE into nerve terminals is already in place by the first week after birth. Consistent with this functional assessment, the mRNA encoding the NE transporter was also expressed in the celiac ganglion at this time. During neonatal-infantile development [postnatal (PN) d 5-20], the spontaneous, vesicle-independent outflow of recently taken up NE was high, but the NE output in response to K(+)-induced depolarization was low. After PN d 20, spontaneous outflow decreased and the response to K(+) increased markedly, reaching maximal values by the time of puberty. Tyramine-mediated displacement of NE stored in vesicles, which displace vesicular NE, showed that vesicle-dependent NE storage becomes functional by PN d 12 and that vesicular release increases during the juvenile-peripubertal phases of sexual development. These results indicate that vesicular release of NE from ovarian noradrenergic nerves begins to operate by the third week of postnatal life, becoming fully functional near the time of puberty.