Advertisement

Nociceptin/Orphanin FQ and Urinary Bladder

  • Patrizia AngelicoEmail author
  • Marco Barchielli
  • Massimo Lazzeri
  • Remo Guerrini
  • Girolamo Caló
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 254)

Abstract

Following identification as the endogenous ligand for the NOP receptor, nociceptin/orphanin FQ (N/OFQ) has been shown to control several biological functions including the micturition reflex. N/OFQ elicits a robust inhibitory effect on rat micturition by reducing the excitability of the afferent fibers. After intravesical administration N/OFQ increases urodynamic bladder capacity and volume threshold in overactive bladder patients but not in normal subjects. Moreover daily treatment with intravesical N/OFQ for 10 days significantly reduced urine leakage episodes. Different chemical modifications were combined into the N/OFQ sequence to generate Rec 0438 (aka UFP-112), a peptide NOP full agonist with high potency and selectivity and long-lasting duration of action. Rec 0438 mimicked the robust inhibitory effects of N/OFQ on rat micturition reflex; its action is solely due to NOP receptor stimulation, does not show tolerance liability after 2 weeks of treatment, and can be elicited by intravesical administration. Collectively the evidence summarized and discussed in this chapter strongly suggests that NOP agonists are promising innovative drugs to treat overactive bladder.

Keywords

Micturition reflex N/OFQ NOP receptor Overactive bladder Rec 0438 

Notes

Declaration of Interests

PA and MB are employed by Recordati S.p.A. RG and GC are among the funders of the University of Ferrara spin-off company UFPeptides s.r.l., the assignee of the patent covering Rec 0438.

Details of Author Contributions PA, ML, and GC wrote the first draft of the chapter, and MB and RG critically revised it. All authors approved the final version of the article.

References

  1. Abdulla FA, Smith PA (1997) Nociceptin inhibits T-type Ca2+ channel current in rat sensory neurons by a G-protein-independent mechanism. J Neurosci 17:8721–8728CrossRefGoogle Scholar
  2. Abdulla FA, Smith PA (1998) Axotomy reduces the effect of analgesic opioids yet increases the effect of nociceptin on dorsal root ganglion neurons. J Neurosci 18:9685–9694CrossRefGoogle Scholar
  3. Anand P et al (2016) Nociceptin/orphanin FQ receptor expression in clinical pain disorders and functional effects in cultured neurons. Pain 157:1960–1969.  https://doi.org/10.1097/j.pain.0000000000000597 CrossRefPubMedGoogle Scholar
  4. Angelico P, Velasco C, Guarneri L, Sironi G, Leonardi A, Testa R (2005) Urodynamic effects of oxybutynin and tolterodine in conscious and anesthetized rats under different cystometrographic conditions. BMC Pharmacol 5:14.  https://doi.org/10.1186/1471-2210-5-14 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Arduin M et al (2007) Synthesis and biological activity of nociceptin/orphanin FQ analogues substituted in position 7 or 11 with Calpha,alpha-dialkylated amino acids. Bioorg Med Chem 15:4434–4443.  https://doi.org/10.1016/j.bmc.2007.04.026 CrossRefPubMedGoogle Scholar
  6. Bigoni R et al (2002) Pharmacological characterisation of [(pX)Phe4]nociceptin(1-13)amide analogues. 1. In vitro studies. Naunyn Schmiedeberg’s Arch Pharmacol 365:442–449.  https://doi.org/10.1007/s00210-002-0548-8 CrossRefGoogle Scholar
  7. Blok BF, Willemsen AT, Holstege G (1997) A PET study on brain control of micturition in humans. Brain J Neurol 120(Pt 1):111–121CrossRefGoogle Scholar
  8. Broccardo M, Guerrini R, Morini G, Polidori C, Agostini S, Petrella C, Improta G (2007) The gastric effects of UFP-112, a new nociceptin/orphanin receptor agonist, in physiological and pathological conditions. Peptides 28:1974–1981.  https://doi.org/10.1016/j.peptides.2007.07.021 CrossRefPubMedGoogle Scholar
  9. Broccardo M, Agostini S, Petrella C, Guerrini R, Improta G (2008) Central and peripheral role of the nociceptin/orphaninFQ system on normal and disturbed colonic motor function and faecal pellet output in the rat. Neurogastroenterol Motil 20:939–948.  https://doi.org/10.1111/j.1365-2982.2008.01120.x CrossRefPubMedGoogle Scholar
  10. Cahill CM, Walwyn W, Taylor AMW, Pradhan AAA, Evans CJ (2016) Allostatic mechanisms of opioid tolerance beyond desensitization and downregulation. Trends Pharmacol Sci 37:963–976.  https://doi.org/10.1016/j.tips.2016.08.002 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Calo G, Bigoni R, Rizzi A, Guerrini R, Salvadori S, Regoli D (2000a) Nociceptin/orphanin FQ receptor ligands. Peptides 21:935–947CrossRefGoogle Scholar
  12. Calo G, Guerrini R, Rizzi A, Salvadori S, Regoli D (2000b) Pharmacology of nociceptin and its receptor: a novel therapeutic target. Br J Pharmacol 129:1261–1283.  https://doi.org/10.1038/sj.bjp.0703219 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Calo G et al (2011) UFP-112 a potent and long-lasting agonist selective for the nociceptin/orphanin FQ receptor. CNS Neurosci Ther 17:178–198.  https://doi.org/10.1111/j.1755-5949.2009.00107.x CrossRefPubMedGoogle Scholar
  14. Camarda V et al (2009) Pharmacological profile of NOP receptors coupled with calcium signaling via the chimeric protein G alpha qi5. Naunyn Schmiedeberg's Arch Pharmacol 379:599–607.  https://doi.org/10.1007/s00210-009-0396-x CrossRefGoogle Scholar
  15. Chapple CR, Khullar V, Gabriel Z, Muston D, Bitoun CE, Weinstein D (2008) The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur Urol 54:543–562.  https://doi.org/10.1016/j.eururo.2008.06.047 CrossRefPubMedGoogle Scholar
  16. Chiou LC, Fan SH, Guerrini R, Calo G (2002) [Nphe(1)]N/OFQ-(1-13)-NH(2) is a competitive and selective antagonist at nociceptin/orphanin FQ receptors mediating K(+) channel activation in rat periaqueductal gray slices. Neuropharmacology 42:246–252CrossRefGoogle Scholar
  17. Chuang YC, Yoshimura N, Huang CC, Chiang PH, Chancellor MB (2004) Intravesical botulinum toxin a administration produces analgesia against acetic acid induced bladder pain responses in rats. J Urol 172:1529–1532CrossRefGoogle Scholar
  18. Connor M, Christie MJ (1998) Modulation of Ca2+ channel currents of acutely dissociated rat periaqueductal grey neurons. J Physiol 509(Pt 1):47–58CrossRefGoogle Scholar
  19. Connor M, Vaughan CW, Chieng B, Christie MJ (1996) Nociceptin receptor coupling to a potassium conductance in rat locus coeruleus neurones in vitro. Br J Pharmacol 119:1614–1618CrossRefGoogle Scholar
  20. D’Agostino B et al (2010) Nociceptin modulates bronchoconstriction induced by sensory nerve activation in mouse lung. Am J Respir Cell Mol Biol 42:250–254.  https://doi.org/10.1165/rcmb.2008-0488OC CrossRefPubMedGoogle Scholar
  21. de Groat WC (1975) Nervous control of the urinary bladder of the cat. Brain Res 87:201–211CrossRefGoogle Scholar
  22. de Groat WC et al (1990) Mechanisms underlying the recovery of urinary bladder function following spinal cord injury. J Auton Nerv Syst 30(Suppl):S71–S77CrossRefGoogle Scholar
  23. de Groat WC, Griffiths D, Yoshimura N (2015) Neural control of the lower urinary tract. Compr Physiol 5:327–396.  https://doi.org/10.1002/cphy.c130056 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Dooley CT, Houghten RA (1996) Orphanin FQ: receptor binding and analog structure activity relationships in rat brain. Life Sci 59:PL23–PL29CrossRefGoogle Scholar
  25. Drake MJ et al (2017) Comparative assessment of the efficacy of onabotulinumtoxinA and oral therapies (anticholinergics and mirabegron) for overactive bladder: a systematic review and network meta-analysis. BJU Int 120:611–622.  https://doi.org/10.1111/bju.13945 CrossRefPubMedGoogle Scholar
  26. Economidou D, Fedeli A, Fardon RM, Weiss F, Massi M, Ciccocioppo R (2006) Effect of novel nociceptin/orphanin FQ-NOP receptor ligands on ethanol drinking in alcohol-preferring msP rats. Peptides 27:3299–3306.  https://doi.org/10.1016/j.peptides.2006.09.007 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Giuliani S, Maggi CA (1996) Inhibition of tachykinin release from peripheral endings of sensory nerves by nociceptin, a novel opioid peptide. Br J Pharmacol 118:1567–1569CrossRefGoogle Scholar
  28. Giuliani S, Maggi CA (1997) Prejunctional modulation by nociceptin of nerve-mediated inotropic responses in guinea-pig left atrium. Eur J Pharmacol 332:231–236CrossRefGoogle Scholar
  29. Giuliani S, Lecci A, Tramontana M, Maggi CA (1999) Nociceptin protects capsaicin-sensitive afferent fibers in the rat urinary bladder from desensitization. Naunyn Schmiedeberg's Arch Pharmacol 360:202–208CrossRefGoogle Scholar
  30. Grandi D, Solenghi E, Guerrini R, Polidori C, Massi M, Morini G (2007) Nociceptin/orphanin FQ prevents gastric damage induced by cold-restraint stress in the rat by acting in the periphery. Peptides 28:1572–1579.  https://doi.org/10.1016/j.peptides.2007.06.019 CrossRefPubMedGoogle Scholar
  31. Guerrini R, Calo G, Rizzi A, Bigoni R, Rizzi D, Regoli D, Salvadori S (2000) Structure-activity relationships of nociceptin and related peptides: comparison with dynorphin A. Peptides 21:923–933CrossRefGoogle Scholar
  32. Guerrini R et al (2001) Structure-activity studies of the Phe(4) residue of nociceptin(1-13)-NH(2): identification of highly potent agonists of the nociceptin/orphanin FQ receptor. J Med Chem 44:3956–3964CrossRefGoogle Scholar
  33. Helyes Z, Nemeth J, Pinter E, Szolcsanyi J (1997) Inhibition by nociceptin of neurogenic inflammation and the release of SP and CGRP from sensory nerve terminals. Br J Pharmacol 121:613–615.  https://doi.org/10.1038/sj.bjp.0701209 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Holzer P (1988) Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides. Neuroscience 24:739–768CrossRefGoogle Scholar
  35. Hu E, Calo G, Guerrini R, Ko MC (2010) Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112. Pain 148:107–113.  https://doi.org/10.1016/j.pain.2009.10.026 CrossRefPubMedGoogle Scholar
  36. Imran M, Najmi AK, Tabrez S (2013) Mirabegron for overactive bladder: a novel, first-in-class beta3-agonist therapy. Urol J 10:935–940PubMedGoogle Scholar
  37. Kalsi V, Apostolidis A, Popat R, Gonzales G, Fowler CJ, Dasgupta P (2006) Quality of life changes in patients with neurogenic versus idiopathic detrusor overactivity after intradetrusor injections of botulinum neurotoxin type A and correlations with lower urinary tract symptoms and urodynamic changes. Eur Urol 49:528–535.  https://doi.org/10.1016/j.eururo.2005.12.012 CrossRefPubMedGoogle Scholar
  38. Kelleher CJ, Cardozo LD, Khullar V, Salvatore S (1997) A medium-term analysis of the subjective efficacy of treatment for women with detrusor instability and low bladder compliance. Br J Obstet Gynaecol 104:988–993CrossRefGoogle Scholar
  39. Kuhtz-Buschbeck JP, van der Horst C, Pott C, Wolff S, Nabavi A, Jansen O, Junemann KP (2005) Cortical representation of the urge to void: a functional magnetic resonance imaging study. J Urol 174:1477–1481CrossRefGoogle Scholar
  40. Lazzeri M et al (2001) Urodynamic and clinical evidence of acute inhibitory effects of intravesical nociceptin/orphanin FQ on detrusor overactivity in humans: a pilot study. J Urol 166:2237–2240CrossRefGoogle Scholar
  41. Lazzeri M et al (2003) Urodynamic effects of intravesical nociceptin/orphanin FQ in neurogenic detrusor overactivity: a randomized, placebo-controlled, double-blind study. Urology 61:946–950CrossRefGoogle Scholar
  42. Lazzeri M et al (2006) Daily intravesical instillation of 1 mg nociceptin/orphanin FQ for the control of neurogenic detrusor overactivity: a multicenter, placebo controlled, randomized exploratory study. J Urol 176:2098–2102.  https://doi.org/10.1016/j.juro.2006.07.025 CrossRefPubMedGoogle Scholar
  43. Lecci A, Giuliani S, Meini S, Maggi CA (2000a) Nociceptin and the micturition reflex. Peptides 21:1007–1021CrossRefGoogle Scholar
  44. Lecci A, Giuliani S, Tramontana M, Criscuoli M, Maggi CA (2000b) Multiple sites of action in the inhibitory effect of nociceptin on the micturition reflex. J Urol 163:638–645CrossRefGoogle Scholar
  45. Leron E, Weintraub AY, Mastrolia SA, Schwarzman P (2018) Overactive bladder syndrome: evaluation and management. Curr Urol 11:117–125.  https://doi.org/10.1159/000447205 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Maggi CA, Meli A (1986) The role of neuropeptides in the regulation of the micturition reflex. J Auton Pharmacol 6:133–162CrossRefGoogle Scholar
  47. Malfacini D et al (2015) Pharmacological profile of nociceptin/orphanin FQ receptors interacting with G-proteins and beta-arrestins 2. PLoS One 10:e0132865.  https://doi.org/10.1371/journal.pone.0132865 CrossRefPubMedPubMedCentralGoogle Scholar
  48. Malfacini D, Simon K, Trapella C, Guerrini R, Zaveri NT, Kostenis E, Calo G (2018) NOP receptor pharmacological profile – a dynamic mass redistribution study. PLoS One 13:e0203021.  https://doi.org/10.1371/journal.pone.020302 CrossRefPubMedGoogle Scholar
  49. Merrill L, Gonzalez EJ, Girard BM, Vizzard MA (2016) Receptors, channels, and signalling in the urothelial sensory system in the bladder. Nat Rev Urol 13:193–204.  https://doi.org/10.1038/nrurol.2016.13 CrossRefPubMedGoogle Scholar
  50. Meunier JC et al (1995) Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377:532–535.  https://doi.org/10.1038/377532a0 CrossRefGoogle Scholar
  51. Micheli L et al (2015a) Acute and subchronic antinociceptive effects of nociceptin/orphanin FQ receptor agonists infused by intrathecal route in rats. Eur J Pharmacol 754:73–81.  https://doi.org/10.1016/j.ejphar.2015.02.020 CrossRefPubMedGoogle Scholar
  52. Micheli L, Di Cesare Mannelli L, Rizzi A, Guerrini R, Trapella C, Calo G, Ghelardini C (2015b) Intrathecal administration of nociceptin/orphanin FQ receptor agonists in rats: a strategy to relieve chemotherapy-induced neuropathic hypersensitivity. Eur J Pharmacol 766:155–162.  https://doi.org/10.1016/j.ejphar.2015.10.005 CrossRefPubMedGoogle Scholar
  53. Nishiguchi J, Hayashi Y, Chancellor MB, de Miguel F, de Groat WC, Kumon H, Yoshimura N (2005) Detrusor overactivity induced by intravesical application of adenosine 5′-triphosphate under different delivery conditions in rats. Urology 66:1332–1337.  https://doi.org/10.1016/j.urology.2005.06.099 CrossRefPubMedGoogle Scholar
  54. Okada K et al (2000) Highly potent nociceptin analog containing the Arg-Lys triple repeat. Biochem Biophys Res Commun 278:493–498.  https://doi.org/10.1006/bbrc.2000.3822 CrossRefPubMedGoogle Scholar
  55. Patel AK, Patterson JM, Chapple CR (2006) Botulinum toxin injections for neurogenic and idiopathic detrusor overactivity: a critical analysis of results. Eur Urol 50:684–709. discussion 709–710.  https://doi.org/10.1016/j.eururo.2006.07.022 CrossRefPubMedGoogle Scholar
  56. Pirazzini M, Rossetto O, Eleopra R, Montecucco C (2017) Botulinum neurotoxins: biology, pharmacology, and toxicology. Pharmacol Rev 69:200–235.  https://doi.org/10.1124/pr.116.012658 CrossRefPubMedPubMedCentralGoogle Scholar
  57. Reinscheid RK et al (1995) Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science 270:792–794CrossRefGoogle Scholar
  58. Rizzi A et al (1999) Nociceptin receptor activation inhibits tachykinergic non adrenergic non cholinergic contraction of guinea pig isolated bronchus. Life Sci 64:PL157–PL163CrossRefGoogle Scholar
  59. Rizzi A et al (2002a) Pharmacological characterisation of [(pX)Phe4]nociceptin(1-13)NH2 analogues. 2. In vivo studies. Naunyn Schmiedeberg's Arch Pharmacol 365:450–456.  https://doi.org/10.1007/s00210-002-0549-7 CrossRefGoogle Scholar
  60. Rizzi D et al (2002b) [Arg(14),Lys(15)]nociceptin, a highly potent agonist of the nociceptin/orphanin FQ receptor: in vitro and in vivo studies. J Pharmacol Exp Ther 300:57–63CrossRefGoogle Scholar
  61. Rizzi A et al (2007a) 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-tetrah ydro-5H-benzocyclohepten-5-ol]: in vivo studies. J Pharmacol Exp Ther 321:968–974.  https://doi.org/10.1124/jpet.106.116780 CrossRefPubMedGoogle Scholar
  62. Rizzi A et al (2007b) In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor. Peptides 28:1240–1251.  https://doi.org/10.1016/j.peptides.2007.04.020 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Schlager TA, Grady R, Mills SE, Hendley JO (2004) Bladder epithelium is abnormal in patients with neurogenic bladder due to myelomeningocele. Spinal Cord 42:163–168.  https://doi.org/10.1038/sj.sc.3101565 CrossRefPubMedGoogle Scholar
  64. Shah S, Page CP, Spina D (1998) Nociceptin inhibits non-adrenergic non-cholinergic contraction in guinea-pig airway. Br J Pharmacol 125:510–516.  https://doi.org/10.1038/sj.bjp.0702068 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Spagnolo B et al (2007) 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-tetrah ydro-5H-benzocyclohepten-5-ol]: in vitro studies. J Pharmacol Exp Ther 321:961–967.  https://doi.org/10.1124/jpet.106.116764 CrossRefPubMedGoogle Scholar
  66. Stewart WF et al (2003) Prevalence and burden of overactive bladder in the United States. World J Urol 20:327–336.  https://doi.org/10.1007/s00345-002-0301-4 CrossRefPubMedGoogle Scholar
  67. Sullo N et al (2013) Nociceptin/orphanin FQ receptor activation decreases the airway hyperresponsiveness induced by allergen in sensitized mice. Am J Physiol Lung Cell Mol Physiol 304:L657–L664.  https://doi.org/10.1152/ajplung.00358.2012 CrossRefPubMedGoogle Scholar
  68. Tancredi T et al (2005) The interaction of highly helical structural mutants with the NOP receptor discloses the role of the address domain of nociceptin/orphanin FQ. Chemistry 11:2061–2070.  https://doi.org/10.1002/chem.200401095 CrossRefPubMedGoogle Scholar
  69. Thiagamoorthy G, Cardozo L, Robinson D (2016) Current and future pharmacotherapy for treating overactive bladder. Expert Opin Pharmacother 17:1317–1325.  https://doi.org/10.1080/14656566.2016.1186645 CrossRefPubMedGoogle Scholar
  70. Tiwari A, Naruganahalli KS (2006) Current and emerging investigational medical therapies for the treatment of overactive bladder. Expert Opin Investig Drugs 15:1017–1037.  https://doi.org/10.1517/13543784.15.9.1017 CrossRefPubMedGoogle Scholar
  71. Vaughan CW, Christie MJ (1996) Increase by the ORL1 receptor (opioid receptor-like1) ligand, nociceptin, of inwardly rectifying K conductance in dorsal raphe nucleus neurones. Br J Pharmacol 117:1609–1611CrossRefGoogle Scholar
  72. Vaughan CW, Ingram SL, Christie MJ (1997) Actions of the ORL1 receptor ligand nociceptin on membrane properties of rat periaqueductal gray neurons in vitro. J Neurosci 17:996–1003CrossRefGoogle Scholar
  73. Warren K, Burden H, Abrams P (2016) Mirabegron in overactive bladder patients: efficacy review and update on drug safety. Ther Adv Drug Saf 7:204–216.  https://doi.org/10.1177/2042098616659412 CrossRefPubMedPubMedCentralGoogle Scholar
  74. Wyndaele JJ (2002) Complications of intermittent catheterization: their prevention and treatment. Spinal Cord 40:536–541.  https://doi.org/10.1038/sj.sc.3101348 CrossRefPubMedGoogle Scholar
  75. Yamada S, Ito Y, Nishijima S, Kadekawa K, Sugaya K (2018) Basic and clinical aspects of antimuscarinic agents used to treat overactive bladder. Pharmacol Ther 189:130–148.  https://doi.org/10.1016/j.pharmthera.2018.04.010 CrossRefPubMedGoogle Scholar
  76. Zaratin PF et al (2004) Modification of nociception and morphine tolerance by the selective opiate receptor-like orphan receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahy dro-5H-benzocyclohepten-5-ol (SB-612111). J Pharmacol Exp Ther 308:454–461.  https://doi.org/10.1124/jpet.103.055848 CrossRefPubMedGoogle Scholar
  77. Zhang C, Miller W, Valenzano KJ, Kyle DJ (2002) Novel, potent ORL-1 receptor agonist peptides containing alpha-Helix-promoting conformational constraints. J Med Chem 45:5280–5286CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Patrizia Angelico
    • 1
    Email author
  • Marco Barchielli
    • 1
  • Massimo Lazzeri
    • 2
  • Remo Guerrini
    • 3
  • Girolamo Caló
    • 4
  1. 1.Pharmaceutical R&D DivisionRecordati S.p.A.MilanItaly
  2. 2.Department of UrologyIstituto Clinico Humanitas IRCCS, Clinical and Research Hospital, RozzanoMilanItaly
  3. 3.Department of Chemical and Pharmaceutical Sciences and LTTAUniversity of FerraraFerraraItaly
  4. 4.Section of Pharmacology, Department of Medical Sciences, and National Institute of NeurosciencesUniversity of FerraraFerraraItaly

Personalised recommendations