Cardio-renal actions of novel nociceptin analogues

Summary

Principal Investigator: DANIEL KAPUSTA
Affiliation: Louisiana State University Health Sciences Center
Country: USA
Abstract: Nociceptin/orphanin FQ (N/OFQ) is an endogenous opioid-like peptide that produces marked effects on cardiovascular (hypotension, bradycardia, sympathoinhibition) and renal excretory (water diuresis) function in animals. Using selective ligands for the N/OFQ peptide receptor (NOP), we have obtained evidence that there exist separate pathways in the brain and periphery by which N/OFQ affects cardiovascular and renal function. As proposed in this application, the development of new ligands (peptide and non-peptide) selective for the NOP receptor, a pertussis toxin-sensitive G-protein receptor, will provide the basic pharmacological tools necessary to systematically study these tissue/system specific pathways. The hypothesis to be tested is that there exist separate central and peripheral NOP receptor pathways that affect cardiovascular and renal function, and that selective activation of the peripheral NOP receptor pathway with novel peptide and non-peptide ligands can evoke a free-water diuresis devoid of adverse cardiovascular/CNS effects. The investigations proposed in this amended application will test this hypothesis using a multidisciplinary approach that can be successfully achieved by the collaborative efforts of two established investigators in the N/OFQ research field, these being the P.I., and Dr. Domenico Regoli. This will entail the synthesis of novel NOP receptor ligands using peptide and non-peptide chemistry, which will be used to elucidate the biological actions, tissue distribution and signal transduction pathways of N/OFQ and NOP receptor ligands in the brain, periphery and kidneys. These studies will employ molecular, cellular and classical pharmacological approaches involving isolated organs, tissues and whole animals; and in vivo analysis of the cardiovascular and renal responses produced by these novel NOP receptor ligands. The use of genetically modified transgenic NOP receptor knockout mice (whole animal/tissue) will provide an innovative approach to understand the effects of N/OFQ and NOP ligands at each site. The pharmacological evaluation of N/OFQ and NOP receptor ligands in different in vitro bioassays and cell culture will explore the pharmacology of the NOP receptor system and the underlying signaling pathways by which NOP receptor ligands elicit diverse cardiovascular and renal responses. Finally, the potential for novel peripherally acting NOP ligands to produce a therapeutic water diuresis in states of vasopressin excess will be explored. It is anticipated that work in this area will provide new strategies for the treatment of different pathological states associated with fluid retention and/or hyponatremia/hypokalemia.
Funding Period: 2003-08-01 - 2010-07-31
more information: NIH RePORT

Top Publications

  1. ncbi 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
    Helmut B Gottlieb
    Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112, USA
    J Pharmacol Exp Ther 312:678-85. 2005
  2. pmc Cytokine blockade attenuates sympathoexcitation in heart failure: cross-talk between nNOS, AT-1R and cytokines in the hypothalamic paraventricular nucleus
    Anuradha Guggilam
    Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, United States
    Eur J Heart Fail 10:625-34. 2008
  3. doi Nociceptin/orphanin FQ (N/OFQ)-evoked bradycardia, hypotension, and diuresis are absent in N/OFQ peptide (NOP) receptor knockout mice
    Melissa A Burmeister
    Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
    J Pharmacol Exp Ther 326:897-904. 2008
  4. pmc Central G-alpha subunit protein-mediated control of cardiovascular function, urine output, and vasopressin secretion in conscious Sprague-Dawley rats
    Richard D Wainford
    Department of Pharmacology, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112, USA
    Am J Physiol Regul Integr Comp Physiol 295:R535-42. 2008
  5. pmc In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor
    Anna Rizzi
    Department of Experimental and Clinical Medicine, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, via Fossato di Mortara 17, 44100 Ferrara, Italy
    Peptides 28:1240-51. 2007
  6. ncbi Centrally administered nociceptin/orphanin FQ (N/OFQ) evokes bradycardia, hypotension, and diuresis in mice via activation of central N/OFQ peptide receptors
    Melissa A Burmeister
    Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA
    J Pharmacol Exp Ther 322:324-31. 2007
  7. ncbi Pharmacological characterization of the nociceptin/orphanin FQ receptor antagonist SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol]: in vitro studies
    Barbara Spagnolo
    Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy
    J Pharmacol Exp Ther 321:961-7. 2007
  8. ncbi Pharmacological characterization of the nociceptin/orphanin FQ receptor antagonist SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol]: in vivo studies
    Anna Rizzi
    Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy
    J Pharmacol Exp Ther 321:968-74. 2007
  9. ncbi In vitro and in vivo pharmacological characterization of the nociceptin/orphanin FQ receptor ligand Ac-RYYRIK-ol
    Ozge Gunduz
    Department of Experimental and Clinical Medicine, Section of Pharmacology and Neuroscience Center, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy
    Eur J Pharmacol 539:39-48. 2006
  10. ncbi Tonic nociceptinergic inputs to neurons in the hypothalamic paraventricular nucleus contribute to sympathetic vasomotor tone and water and electrolyte homeostasis in conscious rats
    Zbigniew K Krowicki
    Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, USA
    J Pharmacol Exp Ther 317:446-53. 2006

Scientific Experts

  • Ozge Gunduz
  • DANIEL KAPUSTA
  • Richard David Wainford
  • Girolamo Calo'
  • Zbigniew K Krowicki
  • Anna Rizzi
  • Domenico Regoli
  • Barbara Spagnolo
  • Girolamo Calo
  • Melissa A Burmeister
  • Claudio Trapella
  • Severo Salvadori
  • Remo Guerrini
  • Helmut B Gottlieb
  • Giuliano Marzola
  • John McDonald
  • Giacomo CarrĂ 
  • David G Lambert
  • Anuradha Guggilam
  • Carmela Fischetti
  • Giulia Fanton
  • Michele Morari
  • Timothy A Barnes
  • Silvia Zucchini
  • G Carra'
  • Velga A Kenigs
  • Masudul Haque
  • Michael A Ansonoff
  • Philip J Ebenezer
  • Joseph Francis
  • John E Pintar
  • Kaushik P Patel
  • Elaine C Gavioli
  • Dave G Lambert
  • Chris Hebbes
  • Martina Fantin
  • Anna Baldisserotto
  • Roberto Ciccocioppo
  • Giacomo Carra'
  • Laura Piccagli
  • Christopher Hebbes
  • Samantha Rubini
  • Flora Mela
  • C Trapella
  • David J Rowbotham
  • Elaine Gavioli
  • Antonio M Cabral
  • Kurt J Varner
  • B Spagnolo
  • D Regoli
  • R Guerrini
  • E Marzola
  • Christopher P Hebbes
  • S Salvadori
  • M Arduin
  • Melissa Burmeister
  • Daniela Rizzi

Detail Information

Publications18

  1. ncbi 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
    Helmut B Gottlieb
    Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112, USA
    J Pharmacol Exp Ther 312:678-85. 2005
    ..Alternatively, central kappa-opioids evoke antinatriuresis via augmenting renal sympathetic nerve activity and/or other neurohumoral sodium retaining pathways at brain sites other than the hypothalamic PVN...
  2. pmc Cytokine blockade attenuates sympathoexcitation in heart failure: cross-talk between nNOS, AT-1R and cytokines in the hypothalamic paraventricular nucleus
    Anuradha Guggilam
    Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, United States
    Eur J Heart Fail 10:625-34. 2008
    ..To investigate evidence for the interplay between cytokines, angiotensin II and nNOS in the paraventricular nucleus (PVN), for regulating sympathetic outflow in a rat model of CHF...
  3. doi Nociceptin/orphanin FQ (N/OFQ)-evoked bradycardia, hypotension, and diuresis are absent in N/OFQ peptide (NOP) receptor knockout mice
    Melissa A Burmeister
    Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
    J Pharmacol Exp Ther 326:897-904. 2008
    ..These results establish that the bradycardia, hypotension and diuresis produced by centrally administered N/OFQ are mediated by selective activation of NOP receptors...
  4. pmc Central G-alpha subunit protein-mediated control of cardiovascular function, urine output, and vasopressin secretion in conscious Sprague-Dawley rats
    Richard D Wainford
    Department of Pharmacology, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112, USA
    Am J Physiol Regul Integr Comp Physiol 295:R535-42. 2008
    ..These findings highlight the novel selective central Galpha-subunit protein-mediated control of cardiovascular vs. renal excretory function...
  5. pmc In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor
    Anna Rizzi
    Department of Experimental and Clinical Medicine, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, via Fossato di Mortara 17, 44100 Ferrara, Italy
    Peptides 28:1240-51. 2007
    ..Collectively, these findings demonstrate that UFP-112 behaves in vitro and in vivo as a highly potent and selective ligand able to produce full and long lasting activation of NOP receptors...
  6. ncbi Centrally administered nociceptin/orphanin FQ (N/OFQ) evokes bradycardia, hypotension, and diuresis in mice via activation of central N/OFQ peptide receptors
    Melissa A Burmeister
    Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA
    J Pharmacol Exp Ther 322:324-31. 2007
    ..injection of the same dose of N/OFQ. Together, these findings demonstrate that in conscious mice, the central administration of N/OFQ evokes marked bradycardia, hypotension, and diuresis by selective activation of central NOP receptors...
  7. ncbi Pharmacological characterization of the nociceptin/orphanin FQ receptor antagonist SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol]: in vitro studies
    Barbara Spagnolo
    Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy
    J Pharmacol Exp Ther 321:961-7. 2007
    ..In conclusion, the results of the present study demonstrated that SB-612111 is among the most potent and NOP-selective nonpeptide antagonists identified to date...
  8. ncbi Pharmacological characterization of the nociceptin/orphanin FQ receptor antagonist SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol]: in vivo studies
    Anna Rizzi
    Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy
    J Pharmacol Exp Ther 321:968-74. 2007
    ..The use of SB-612111 in future pathophysiological studies will certainly contribute to define the therapeutic potential of selective NOP receptor antagonists in different disease areas...
  9. ncbi In vitro and in vivo pharmacological characterization of the nociceptin/orphanin FQ receptor ligand Ac-RYYRIK-ol
    Ozge Gunduz
    Department of Experimental and Clinical Medicine, Section of Pharmacology and Neuroscience Center, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy
    Eur J Pharmacol 539:39-48. 2006
    ..The high potency, selectivity of action, and in vivo effectiveness make Ac-RYYRIK-ol a useful pharmacological tool for future studies in the field of N/OFQ and its NOP receptor...
  10. ncbi Tonic nociceptinergic inputs to neurons in the hypothalamic paraventricular nucleus contribute to sympathetic vasomotor tone and water and electrolyte homeostasis in conscious rats
    Zbigniew K Krowicki
    Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, USA
    J Pharmacol Exp Ther 317:446-53. 2006
    ..Moreover, UFP-101 blocks a tonically active inhibitory influence of endogenous N/OFQ on central sympathetic outflow and vasopressin pathways which arise from the PVN to affect heart rate and urine output...
  11. ncbi Identification of an achiral analogue of J-113397 as potent nociceptin/orphanin FQ receptor antagonist
    Claudio Trapella
    Department of Pharmaceutical Sciences, Biotechnology Center, University of Ferrara, 44100 Ferrara, Italy
    Bioorg Med Chem 14:692-704. 2006
    ..The compound coded as Trap-101, an achiral analogue of J-113397, combines a pharmacological profile similar to that of the parent compound with a practical, high-yielding preparation...
  12. ncbi UFP-101, a peptide antagonist selective for the nociceptin/orphanin FQ receptor
    Girolamo Calo
    Department Experimental and Clinical Medicine, Section of Pharmacology and Neuroscience Centre, University of Ferrara, Via Fossato di Mortara, 19, 44100 Ferrara, Italy
    CNS Drug Rev 11:97-112. 2005
    ....
  13. ncbi Endogenous central kappa-opioid systems augment renal sympathetic nerve activity to maximally retain urinary sodium during hypotonic saline volume expansion
    Helmut B Gottlieb
    Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, Louisiana 70112, USA
    Am J Physiol Regul Integr Comp Physiol 289:R1289-96. 2005
    ....
  14. ncbi Tryptophan replacement in the nociceptin/orphanin FQ receptor ligand Ac-RYYRWK-NH2
    G Carra'
    Section of Pharmacology and Neuroscience Centre, Department of Experimental and Clinical Medicine, University of Ferrara, 44100 Ferrara, Italy
    J Pept Res 66:39-47. 2005
    ....
  15. ncbi Functional selectivity of nociceptin/orphanin FQ peptide receptor partial agonists on cardiovascular and renal function
    Daniel R Kapusta
    Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112, USA
    J Pharmacol Exp Ther 314:643-51. 2005
    ..c.v., cardiovascular depressor; i.c.v. and i.v., water diuresis), partial agonist (i.v., submaximal hypotension) to antagonist (i.v., blockade of N/OFQ-evoked bradycardia and hypotension) behavior...
  16. ncbi Pharmacodynamic characterization of ZP120 (Ac-RYYRWKKKKKKK-NH2), a novel, functionally selective nociceptin/orphanin FQ peptide receptor partial agonist with sodium-potassium-sparing aquaretic activity
    Daniel R Kapusta
    Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112, USA
    J Pharmacol Exp Ther 314:652-60. 2005
    ....
  17. ncbi [(pF)Phe4,Arg14,Lys15]N/OFQ-NH2 (UFP-102), a highly potent and selective agonist of the nociceptin/orphanin FQ receptor
    Giacomo CarrĂ 
    Department of Experimental and Clinical Medicine, Section of Pharmacology, via Fossato di Mortara 19, 44100 Ferrara, Italy
    J Pharmacol Exp Ther 312:1114-23. 2005
    ..These effects were comparable with those evoked by N/OFQ at 5 nmol. Collectively, these findings demonstrate that UFP-102 behaves as a highly potent and selective NOP receptor agonist that produces long-lasting effects in vivo...
  18. pmc Chronic high-NaCl intake prolongs the cardiorenal responses to central N/OFQ and produces regional changes in the endogenous brain NOP receptor system
    Richard D Wainford
    Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112, USA
    Am J Physiol Regul Integr Comp Physiol 296:R280-8. 2009
    ....