The high density of k-opioid receptors in the hypothalamus and the high concentration of Dyn peptides in both hypothalamus and pituitary suggest a possible involvement of Dyn in neuroendocrine regulation. Recent studies in the ovine fetus have led us to propose that Dyn is an important secretagogue of ACTH, and that Dyn may act via non-opioid as well as opioid mechanisms. Specifically, we hypothesize that Dyn releases ACTH via two different, but complementary, pathways. Dyn can act on k-opioid receptors in the hypothalamus to release CRH and AVP. In addition, it is hypothesized that Dyn is co-released with AVP and CRH from the hypothalamus, and this Dyn pool can then act on non-opioid receptors in the anterior pituitary to release ACTH and b-endorphin (bEnd). The goal of this project is to understand the regulatory control of both opioid and non-opioid pathways involved in the release of ACTH and bEnd by Dyn.
Our specific aims are: 1) To understand the mechanisms behind the non-opioid actions of Dyn in the anterior pituitary. We hypothesize that Dyn and/or its metabolite(s) may act via the NMDA receptor or via a novel unidentified receptor in the anterior pituitary. To gain some insight into the structural specificity of this receptor, we plan to compare the activity of a number of Dyn-related peptides; 2) To determine if tolerance develops to both the opioid and non-opioid component of Dyn's action with repeated Dyn exposure. We hypothesize that tolerance will only develop to the hypothalamic opioid component and that NMDA plays a role in mediating this process; 3) To determine if cortisol plays a negative feedback role in down-regulating the opioid and non-opioid component of Dyn's action. We hypothesize that only the hypothalamic opioid component will be subjected to negative feedback control by cortisol. A combination of in vivo (chronically-instrumented ovine fetus preparation) and in vitro (primary cultures of ovine fetal anterior pituitary cells) techniques will be used. The proposed studies will significantly enhance our understanding of the role of Dyn in neuroendocrine function and the regulatory control of its complex mechanisms of action. Besides sharing the common theme of non-opioid actions of Dyn A, this component will share active interaction with all other components. Dr. Lee will provide the Dyn-related peptides for structure-activity studies; Dr. Hook will advise us on the relevant endogenous Dyn-related peptides to be tested for ACTH release; our data will be provided to Dr. Weinstein for molecular modeling.
|Szeto, Hazel H (2003) Dynorphin and the hypothalamo-pituitary-adrenal axis during fetal development. Life Sci 73:749-58|
|Sankararamakrishnan, R; Weinstein, H (2000) Molecular dynamics simulations predict a tilted orientation for the helical region of dynorphin A(1-17) in dimyristoylphosphatidylcholine bilayers. Biophys J 79:2331-44|