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Submitted on September 29, 2003
Accepted on February 17, 2004
Department of Physiology and Pharmacology, West Virginia University Health Sciences Center, Morgantown, WV 26506-9229; Department of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521
* To whom correspondence should be addressed. E-mail: bgoodman{at}hsc.wvu.edu.
Endogenous opioid peptides (EOP) mediate progesterone negative feedback in many species, but the specific EOP systems involved remain unresolved. We first addressed this question in sheep by determining the role of different EOP receptor subtypes in the medial basal hypothalamus (MBH) and preoptic area (POA). Local administration of EOP receptor antagonists to luteal phase ewes indicated that 
-, but not µ- or 
-, receptors mediate the inhibition of LH secretion in the MBH. In contrast, both - and µ-, but not -receptor, antagonists increased LH pulse frequency when placed in the POA. We next examined close appositions between dynorphin ( ligand) and 
-endorphin (µ ligand) containing varicosities and gonadotropin-releasing hormone (GnRH) perikarya in luteal phase ewes using dual immunocytochemistry and light microscopy. Approximately 90% of MBH GnRH neurons had close associations by dynorphin-containing varicosities, but only 40-50% of GnRH perikarya elsewhere had such close associations. In contrast, the percentage of -endorphinergic varicosities close to GnRH neurons was similar among all regions. Electron microscopic analysis demonstrated both dynorphinergic synapses and -endorphinergic synapses onto GnRH perikarya. These and other data, lead to the hypothesis that dynorphin neurons play a major role in progesterone negative feedback in the ewe and that this inhibition may be exerted directly upon GnRH perikarya within the MBH, while dynorphin and -endorphin input to GnRH neurons in the POA provide redundancy to this system or are involved in other actions of progesterone or estradiol in the control of the GnRH surge.
-endorphin •
kappa receptors •
mu receptors •
GnRH •
progesterone negative feedback
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