Central mu- and kappa-opioid agonists evoke profound changes in urine flow rate and urinary sodium excretion via multiple integrated neural and physiological mechanisms. In addition to these subtypes, a novel opioid-like peptide, nociceptin, and opioid receptor, the ORL1 receptor, have recently been identified. Despite their structural resemblance to endogenous opioid peptides and receptors, the role of nociceptin and the ORL1 receptor in the regulation of renal function, is not known. My short-term goals are to characterize the renal responses produced by activation of the central nociceptin system on renal hemodynamic and excretory function in conscious Sprague-Dawley rats. In addition, the neural and humoral mechanisms, as well as brain sites (e.g. paraventricular nucleus) by which this novel central opioid-like system affects renal function will be investigated. My long-term objectives are to understand the physiological role of the endogenous central nociceptin system in the regulation of renal function and determine how this system interacts with classical opioid systems in this regulatory process. Since to date an antagonist for the ORL1 receptor has not been developed, the role of the endogenous central nociceptin system in the regulation of renal function during basal and stressful environmental conditions will be examined by use of in vivo molecular biology techniques (antisense oligodeoxynucleotide). The funding of an RCDA will help me to accomplish the goals outlined above and to further develop and strengthen my scientific career. In this regard, an RCDA will relieve me from Departmental obligations such as teaching in medical, dental, nursing and allied health courses, and from my substantial duties as Graduate Coordinator for the Department of Pharmacology. I will also be exempt from service on additional committees, both at the Departmental and University level. Together, by securing this award I will be able to devote essentially a full-time effort to my cardiovascular and renal research. The Department of Pharmacology and LSU Medical center provide a supportive environment for the development of my research career. Service is available from the LSUMC Biotechnology Unit for the synthesis of the antisense oligodeoxynucleotides. Facilities are also available within the University for computer and statistical consultation. There also exists a number of other basic research and clinical scientists that maintain active research programs in cardiovascular and renal physiology. The fact that Department faculty receive considerable support from federal granting agencies means that expertise and equipment is readily available. In summary, an RCDA will greatly enhance my research productivity and scientific career.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02DK002605-04
Application #
6476012
Study Section
Special Emphasis Panel (SRC)
Program Officer
Rankin, Tracy L
Project Start
1999-03-01
Project End
2003-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
4
Fiscal Year
2002
Total Cost
$100,440
Indirect Cost
Name
Louisiana State University Hsc New Orleans
Department
Pharmacology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Burmeister, Melissa A; Ansonoff, Michael A; Pintar, John E et al. (2008) Nociceptin/orphanin FQ (N/OFQ)-evoked bradycardia, hypotension, and diuresis are absent in N/OFQ peptide (NOP) receptor knockout mice. J Pharmacol Exp Ther 326:897-904
Burmeister, Melissa A; Kapusta, Daniel R (2007) Centrally administered nociceptin/orphanin FQ (N/OFQ) evokes bradycardia, hypotension, and diuresis in mice via activation of central N/OFQ peptide receptors. J Pharmacol Exp Ther 322:324-31
Krowicki, Zbigniew K; Kapusta, Daniel R (2006) Tonic nociceptinergic inputs to neurons in the hypothalamic paraventricular nucleus contribute to sympathetic vasomotor tone and water and electrolyte homeostasis in conscious rats. J Pharmacol Exp Ther 317:446-53
Carra, Giacomo; Rizzi, Anna; Guerrini, Remo et al. (2005) [(pF)Phe4,Arg14,Lys15]N/OFQ-NH2 (UFP-102), a highly potent and selective agonist of the nociceptin/orphanin FQ receptor. J Pharmacol Exp Ther 312:1114-23
Gottlieb, Helmut B; Varner, Kurt J; Kenigs, Velga A et al. (2005) Differential cardiovascular and renal responses produced by microinjection of the {kappa}-opioid U-50488H [(trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzene-acetamide) methane sulfonate] into subregions of the paraventricular nucleus. J Pharmacol Exp Ther 312:678-85
Kapusta, Daniel R; Thorkildsen, Christian; Kenigs, Velga A et al. (2005) Pharmacodynamic characterization of ZP120 (Ac-RYYRWKKKKKKK-NH2), a novel, functionally selective nociceptin/orphanin FQ peptide receptor partial agonist with sodium-potassium-sparing aquaretic activity. J Pharmacol Exp Ther 314:652-60
Gottlieb, Helmut B; Kapusta, Daniel R (2005) Endogenous central kappa-opioid systems augment renal sympathetic nerve activity to maximally retain urinary sodium during hypotonic saline volume expansion. Am J Physiol Regul Integr Comp Physiol 289:R1289-96
Kapusta, Daniel R; Burmeister, Melissa A; Calo', Girolamo et al. (2005) Functional selectivity of nociceptin/orphanin FQ peptide receptor partial agonists on cardiovascular and renal function. J Pharmacol Exp Ther 314:643-51
Kapusta, Daniel R; Dayan, Lisa A; Kenigs, Velga A (2002) Nociceptin/orphanin FQ modulates the cardiovascular, but not renal, responses to stress in spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 29:254-9
Menegaz, R G; Kapusta, D R; Mauad, H et al. (2001) Activation of alpha(2)-receptors in the rostral ventrolateral medulla evokes natriuresis by a renal nerve mechanism. Am J Physiol Regul Integr Comp Physiol 281:R98-R107

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