title: 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.
authors.affiliation: Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Nakahara
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Uenoyama
authors.forename: Akira
authors.initials: A
authors.lastname: Iwase
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Sho
authors.initials: S
authors.lastname: Nakamura
authors.forename: Shiori
authors.initials: S
authors.lastname: Minabe
authors.forename: Youki
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Chikaya
authors.initials: C
authors.lastname: Deura
authors.forename: Taro
authors.initials: T
authors.lastname: Noguchi
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kikkawa
authors.forename: Kei-ichiro
authors.initials: K
authors.lastname: Maeda
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tsukamura
mesh_terms: D000818:Animals; D004343:Drug Implants; D004399:Dynorphins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism*; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015287:Neurokinin B / Q000819:agonists / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010053:Ovary / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000633:toxicity; D011629:Puberty, Precocious / Q000097:blood / Q000139:chemically induced / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018042:Receptors, Neurokinin-3 / Q000819:agonists / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012741:Sexual Maturation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013373:Substance P / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity; D014886:Weaning
chemical_list: D004343:Drug Implants; D009292:Narcotic Antagonists; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D018042:Receptors, Neurokinin-3; D017473:Receptors, Opioid, kappa; C054724:senktide; D013373:Substance P; C051844:norbinaltorphimine; D009271:Naltrexone; D004399:Dynorphins; D015287:Neurokinin B; D007986:Luteinizing Hormone