Dynorphin and Kappa-Opioid Receptor-Mediated Regulation of the Ovulatory Luteinizing Hormone Surge

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Robert Gallo IBN 9807546 A decrease in the inhibitory influence of endogenous opioid peptides on luteinizing hormone (LH) secretion is important in the regulation of the ovulatory LH surge. This suppression is postulated to be exerted by beta-endorphin originating in arcuate nucleus neurons and acting via mu- opioid receptors. The potential involvement of other opioid peptides and their receptors in "disinhibition" of the LH surge has not been explored. Recent work in Dr. Gallo's lab suggests that reduction in medial preoptic area (MPOA) kappa- opioid receptor-mediated inhibitory tone may be a critical event in the generation of the LH surge. This proposal has two specific aims designed to clarify the mechanisms underlying MPOA kappa-opioid receptor-mediated suppression of the LH surge. (1) Because dynorphin is the endogenous ligand for the kappa-opioid receptor, the first aim will be to determine which of the end products of prodynorphin processing are the active ligands in the MPOA mediating suppression of LH secretion. (2) The second aim will be to determine whether reduction in MPOA kappa-opioid receptor- mediated suppression of the LH surge is due to a decrease in the number of kappa-opioid receptors, the affinity of the kappa receptors for its endogenous ligand, and/or the synthesis of prodynorphin in the MPOA preceding the LH surge. These experiments will broaden our understanding of the role of the prodynorphin family of opioid peptides in reproductive neuroendocrine function by clarifying their role in the mechanisms regulating the ovulatory LH surge.