Changes in the pulsatile secretion of gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH) are critical for the regulation of events leading to ovulation, as well as to the inhibition of ovulation prior to puberty and during other physiological periods of infertility. Endogenous opioid peptides (EOPs) have been known for many years to suppress pulsatile secretion of GnRH and LH, specifically mediating the negative feedback influence of progesterone. Findings in the past grant period have provided evidence that one type of EOP system, the dynorphin system, plays a key role in the control of GnRH pulses. Specifically, we have identified three sub-populations of dynorphin neurons that contain progesterone receptors, in the preoptic area, anterior hypothalamus and arcuate nucleus of the hypothalamus, which are strong candidates for mediating the negative feedback influence of progesterone. Based on these findings, we now propose to determine which of these sub-populations (1) send direct projections to GnRH cells; and (2) mediate the negative feedback actions of progesterone. In addition, we recently discovered that orphanin FQ (OFQ), an EOP not previously known to play a role in reproduction, is co-localized in almost all GnRH neurons, including their fibers in the median eminence and have preliminary evidence that OFQ inhibits episodic LH secretion. Hence, we will also explore the role of OFQ in control of episodic LH and GnRH secretion. These questions will be explored using the sheep as an animal model because of advantages that include the similarity of its estrous cycle to the human menstrual cycle and the ability to directly monitor GnRH pulses without anesthesia. In addition, EOPs have been shown to play a major role in mediating progesterone negative feedback during the luteal phase in humans as well as sheep. Thus, these studies may lay the foundation for the development of better treatments for pathological disruptions of reproductive function, and the basis for the design of novel contraceptive techniques. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD039916-05A1
Application #
7149940
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Lamar, Charisee A
Project Start
2006-09-01
Project End
2011-07-31
Budget Start
2006-09-01
Budget End
2007-07-31
Support Year
5
Fiscal Year
2006
Total Cost
$270,154
Indirect Cost
Name
University of Western Ontario
Department
Type
DUNS #
208469452
City
London
State
ON
Country
Canada
Zip Code
N6 3-K7
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Nestor, Casey C; Bedenbaugh, Michelle N; Hileman, Stanley M et al. (2018) Regulation of GnRH pulsatility in ewes. Reproduction 156:R83-R99
Moore, Aleisha M; Lucas, Kathryn A; Goodman, Robert L et al. (2018) Three-dimensional imaging of KNDy neurons in the mammalian brain using optical tissue clearing and multiple-label immunocytochemistry. Sci Rep 8:2242
McCosh, Richard B; Szeligo, Brett M; Bedenbaugh, Michelle N et al. (2017) Evidence That Endogenous Somatostatin Inhibits Episodic, but Not Surge, Secretion of LH in Female Sheep. Endocrinology 158:1827-1837
Grachev, P; Porter, K L; Coolen, L M et al. (2016) Surge-Like Luteinising Hormone Secretion Induced by Retrochiasmatic Area NK3R Activation is Mediated Primarily by Arcuate Kisspeptin Neurones in the Ewe. J Neuroendocrinol 28:
Fergani, Chrysanthi; Mazzella, Leanne; Coolen, Lique M et al. (2016) Do Substance P and Neurokinin A Play Important Roles in the Control of LH Secretion in Ewes? Endocrinology 157:4829-4841
Weems, Peyton W; Witty, Christine F; Amstalden, Marcel et al. (2016) ?-Opioid Receptor Is Colocalized in GnRH and KNDy Cells in the Female Ovine and Rat Brain. Endocrinology 157:2367-79
Merkley, C M; Coolen, L M; Goodman, R L et al. (2015) Evidence for Changes in Numbers of Synaptic Inputs onto KNDy and GnRH Neurones during the Preovulatory LH Surge in the Ewe. J Neuroendocrinol 27:624-35
Goodman, Robert L; Coolen, Lique M; Lehman, Michael N (2014) A role for neurokinin B in pulsatile GnRH secretion in the ewe. Neuroendocrinology 99:18-32
Porter, K L; Hileman, S M; Hardy, S L et al. (2014) Neurokinin-3 receptor activation in the retrochiasmatic area is essential for the full pre-ovulatory luteinising hormone surge in ewes. J Neuroendocrinol 26:776-84

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