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

内源性阿片肽对促黄体生成素（LH）分泌抑制作用的降低在排卵期LH激增的调节中是重要的。这种抑制被认为是由起源于弓形核神经元并通过mu-阿片受体起作用的-内啡肽施加的。其他阿片肽及其受体在LH激增的“去抑制”中的潜在参与尚未被探索。Gallo博士实验室最近的研究表明，内侧视前区（MPOA） kappa-阿片受体介导的抑制性张力的降低可能是黄体生成素激增产生的一个关键事件。该建议有两个具体目的，旨在阐明MPOA kappa-阿片受体介导的LH激增抑制的机制。(1)由于促啡肽是kappa-阿片受体的内源性配体，因此第一个目标将是确定哪些促啡肽加工的最终产物是MPOA介导LH分泌抑制的活性配体。(2)第二个目的将是确定MPOA中kappa-阿片受体介导的LH激增抑制的减少是否由于kappa-阿片受体数量的减少，kappa受体与其内源性配体的亲和力，和/或在LH激增之前MPOA中prodynorphin的合成。这些实验将通过阐明它们在调节排卵促黄体生成素激增中的作用机制，拓宽我们对阿片肽前啡肽家族在生殖神经内分泌功能中的作用的理解。

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.