Evidence that orphanin FQ mediates progesterone negative feedback in the ewe.
Orphanin FQ (OFQ), a member of the opioid family, is found in many areas of the hypothalamus and, when given centrally OFQ inhibits episodic LH secretion in rodents and sheep. Because GnRH neurons are devoid of the appropriate receptors to mediate steroid negative feedback directly, neurons that release OFQ may be involved. Using immunocytochemistry, we first determined that most OFQ neurons in the arcuate nucleus (ARC) and other hypothalamic regions of luteal phase ewes contained both estrogen receptor α and progesterone (P) receptor. Given a similar high degree of steroid receptor colocalization in other ARC subpopulations, we examined whether OFQ neurons of the ARC contained those other neuropeptides and neurotransmitters. OFQ did not colocalize with kisspeptin, tyrosine hydroxylase, or agouti-related peptide, but all ARC OFQ neurons coexpressed proopiomelanocortin. To test for a role for endogenous OFQ, we examined the effects of an OFQ receptor antagonist, [Nphe1,Arg14,Lys15]Nociceptin-NH2 (UFP-101) (30 nmol intracerebroventricular/h), on LH secretion in steroid-treated ewes in the breeding season and ovary-intact ewes in anestrus. Ovariectomized ewes with luteal phase concentrations of P and estradiol showed a significant increase in LH pulse frequency during infusion of UFP-101 (4.5 ± 0.5 pulses/6 h) compared with saline infusion (2.6 ± 0.4 pulses/6 h), whereas ewes implanted with only estradiol did not. Ovary-intact anestrous ewes displayed no significant differences in LH pulse amplitude or frequency during infusion of UFP-101. Therefore, we conclude that OFQ mediates, at least in part, the negative feedback action of P on GnRH/LH pulse frequency in sheep.
Department of Physiology and Pharmacology, PO Box 9229, West Virginia University, Morgantown, West Virginia 26506. rgoodman@hsc.wvu.edu.
Casey C
CC
Nestor
Lique M
LM
Coolen
Gail L
GL
Nesselrod
Miro
M
Valent
John M
JM
Connors
Stanley M
SM
Hileman
Guanliang
G
Cheng
Michael N
MN
Lehman
Robert L
RL
Goodman
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000378:metabolism; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004971:Estrus; D025461:Feedback, Physiological; D005260:Female; D007031:Hypothalamus / Q000378:metabolism; D007986:Luteinizing Hormone / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018847:Opioid Peptides / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D010052:Ovariectomy; D011374:Progesterone / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D021381:Protein Transport; D011980:Receptors, Progesterone / Q000378:metabolism; D012756:Sheep / Q000502:physiology*; D000097629:Nociceptin
D004958:Estradiol; D047628:Estrogen Receptor alpha; D007986:Luteinizing Hormone; D018847:Opioid Peptides; D011374:Progesterone; D011980:Receptors, Progesterone; D000097629:Nociceptin; C479838:(Nphe(1),Arg(14),Lys(15))N-OFQ NH(2)