Journal of Anesthesia

, Volume 28, Issue 5, pp 759–767 | Cite as

Nociceptin system as a target in sepsis?

  • Róisín Thomas
  • Cordula Stover
  • David G. Lambert
  • Jonathan P. Thompson
Invited Review Article

Abstract

The nociceptin system comprises the nociceptin receptor (NOP) and the ligand nociceptin/orphanin FQ (N/OFQ) that binds to the receptor. The archetypal role of the system is in pain processing but the NOP receptor is also expressed on immune cells. Activation of the NOP receptor is known to modulate inflammatory responses, such as mast-cell degranulation, neutrophil rolling, vasodilation, increased vascular permeability, adhesion molecule regulation and leucocyte recruitment. As there is a loss of regulation of inflammatory responses during sepsis, the nociceptin system could be a target for therapies aimed at modulating sepsis. This review details the known effects of NOP activation on leucocytes and the vascular endothelium and discusses the most recent human and animal data on the role of the nociceptin system in sepsis.

Keywords

Nociceptin N/OFQ ppNoc NOP Sepsis 

References

  1. 1.
    Sriskandan S, Altmann D. The immunology of sepsis. J Pathol. 2008;214:211–23.PubMedCrossRefGoogle Scholar
  2. 2.
    Jawad I, Lukšić I, Rafnsson SB. Assessing available information on the burden of sepsis: global estimates of incidence, prevalence and mortality. J Glob Health. 2012;2:010404.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther. 2012;10:701–6.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Vincent J-L, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall J-R, Payen D. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34:344–53.PubMedCrossRefGoogle Scholar
  5. 5.
    Serrano-Gomez A, Thompson J, Lambert D. Nociceptin/orphanin FQ in inflammation and sepsis. Br J Anaesth. 2011;106:6–12.PubMedCrossRefGoogle Scholar
  6. 6.
    Gavioli EC, Romao PR. NOP receptor ligands as potential agents for inflammatory and autoimmune diseases. J Amino Acids. 2011;2011:836569.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Reinscheid RK, Nothacker H-P, Bourson A, Ardati A, Henningsen RA, Bunzow JR, Grandy DK, Langen H, Monsma FJ, Civelli O. Orphanin FQ: a neuropeptide that activates an opioid like G protein-coupled receptor. Science. 1995;270:792–4.PubMedCrossRefGoogle Scholar
  8. 8.
    Lambert DG. The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential. Nat Rev Drug Discov. 2008;7:694–710.PubMedCrossRefGoogle Scholar
  9. 9.
    Pampusch MS, Serie JR, Osinski MA, Seybold VS, Murtaugh MP, Brown DR. Expression of nociceptin/OFQ receptor and prepro-nociceptin/OFQ in lymphoid tissues. Peptides. 2000;21:1865–70.PubMedCrossRefGoogle Scholar
  10. 10.
    Arjomand J, Cole S, Evans CJ. Novel orphanin FQ/nociceptin transcripts are expressed in human immune cells. J Neuroimmunol. 2002;130:100–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Miller TR, Fulford AJ. Regulation of nociceptin/orphanin FQ secretion by immune cells and functional modulation of interleukin-2. Peptides. 2007;28:2243–52.PubMedCrossRefGoogle Scholar
  12. 12.
    Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent J-L, Ramsay G. 2001 sccm/esicm/accp/ats/sis international sepsis definitions conference. Intensive Care Med. 2003;29:530–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Kimura T, Kitaichi K, Hiramatsu K, Yoshida M, Ito Y, Kume H, Yamaki K, Suzuki R, Takagi K. Intradermal application of nociceptin increases vascular permeability in rats: the possible involvement of histamine release from mast cells. Eur J Pharmacol. 2000;407:327–32.PubMedCrossRefGoogle Scholar
  14. 14.
    Adib-Conquy M, Cavaillon J-M. Stress molecules in sepsis and systemic inflammatory response syndrome. FEBS Lett. 2007;581:3723–33.PubMedCrossRefGoogle Scholar
  15. 15.
    Jean-Baptiste E. Cellular mechanisms in sepsis. J Intensive Care Med. 2007;22:63–72.PubMedCrossRefGoogle Scholar
  16. 16.
    Marshall JS, Jawdat DM. Mast cells in innate immunity. J Allergy Clin Immunol. 2004;114:21–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood. 2003;101:3765–77.PubMedCrossRefGoogle Scholar
  18. 18.
    Brookes ZL, Stedman EN, Guerrini R, Lawton BK, Calo G, Lambert DG. Proinflammatory and vasodilator effects of nociceptin/orphanin FQ in the rat mesenteric microcirculation are mediated by histamine. Am J Physiol Heart Circ Physiol. 2007;293:H2977–85.PubMedCrossRefGoogle Scholar
  19. 19.
    Calo G, Guerrini R, Rizzi A, Salvadori S, Burmeister M, Kapusta DR, Lambert DG, Regoli D. UFP-101, a peptide antagonist selective for the nociceptin/orphanin FQ receptor. CNS Drug Rev. 2005;11:97–112.PubMedCrossRefGoogle Scholar
  20. 20.
    Brookes ZL, Stedman EN, Brown NJ, Hebbes CP, Guerrini R, Calo G, Reilly CS, Lambert DG. The nociceptin/orphanin FQ receptor antagonist UFP-101 reduces microvascular inflammation to lipopolysaccharide in vivo. PLoS One. 2013;8:e74943.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Serhan CN, Fierro IM, Chiang N, Pouliot M. Cutting edge: nociceptin stimulates neutrophil chemotaxis and recruitment: inhibition by aspirin-triggered-15-epi-lipoxin A4. J Immunol. 2001;166:3650–4.PubMedCrossRefGoogle Scholar
  22. 22.
    Kato S, Tsuzuki Y, Hokari R, Okada Y, Miyazaki J, Matsuzaki K, Iwai A, Kawaguchi A, Nagao S, Itoh K, Suzuki H, Nabeshima T, Miura S. Role of nociceptin/orphanin FQ (Noc/oFQ) in murine experimental colitis. J Neuroimmunol. 2005;161:21–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Fink M, Evans T. Mechanisms of organ dysfunction in critical illness: report from a Round Table Conference held in Brussels. Intensive Care Med. 2002;28:369–75.PubMedCrossRefGoogle Scholar
  24. 24.
    Astiz ME, DeGent GE, Lin RY, Rackow EC. Microvascular function and rheologic changes in hyperdynamic sepsis. Crit Care Med. 1995;23:265–71.PubMedCrossRefGoogle Scholar
  25. 25.
    Trombella S, Vergura R, Falzarano S, Guerrini R, Calo G, Spisani S. Nociceptin/orphanin FQ stimulates human monocyte chemotaxis via NOP receptor activation. Peptides. 2005;26:1497–502.PubMedCrossRefGoogle Scholar
  26. 26.
    Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF. Neutrophils in development of multiple organ failure in sepsis. Lancet. 2006;368:157–69.PubMedCrossRefGoogle Scholar
  27. 27.
    Thompson JP, Serrano-Gomez A, McDonald J, Ladak N, Bowrey S, Lambert DG. The nociceptin/orphanin FQ system is modulated in patients admitted to ICU with sepsis and after cardiopulmonary bypass. PLoS One. 2013;8:e76682.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Cohen J. The immunopathogenesis of sepsis. Nature. 2002;420:885–91.PubMedCrossRefGoogle Scholar
  29. 29.
    Jimenez MF, Watson RWG, Parodo J, Evans D, Foster D, Steinberg M, Rotstein OD, Marshall JC. Dysregulated expression of neutrophil apoptosis in the systemic inflammatory response syndrome. Arch Surg. 1997;132:1263.PubMedCrossRefGoogle Scholar
  30. 30.
    Colotta F, Re F, Polentarutti N, Sozzani S, Mantovani A. Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products. Blood. 1992;80:2012–20.PubMedGoogle Scholar
  31. 31.
    Otsuka Y, Nagano K, Hori K, Oh-ishi J, Hayashi H, Watanabe N, Niitsu Y. Inhibition of neutrophil migration by tumor necrosis factor. Ex vivo and in vivo studies in comparison with in vitro effect. J Immunol. 1990;145:2639–43.PubMedGoogle Scholar
  32. 32.
    Martins PS, Kallas EG, Neto MC, Dalboni MA, Blecher S, Salomao R. Upregulation of reactive oxygen species generation and phagocytosis, and increased apoptosis in human neutrophils during severe sepsis and septic shock. Shock. 2003;20:208–12.PubMedCrossRefGoogle Scholar
  33. 33.
    Simms H, D’amico R. Polymorphonuclear leukocyte dysregulation during the systemic inflammatory response syndrome. Blood. 1994;83:1398–407.PubMedGoogle Scholar
  34. 34.
    Nakamori Y, Koh T, Ogura H, Tanaka H, Fujimi S, Kasai K, Hosotubo H, Shimazu T, Sugimoto H. Enhanced Expression of Intranuclear NF-[kappa] B in Primed Polymorphonuclear Leukocytes in Systemic Inflammatory Response Syndrome Patients. J Trauma Acute Care Surg. 2003;54:253–60.CrossRefGoogle Scholar
  35. 35.
    Williams JP, Thompson JP, Young SP, Gold SJ, McDonald J, Rowbotham DJ, Lambert DG. Nociceptin and urotensin-II concentrations in critically ill patients with sepsis. Br J Anaesth. 2008;100:810–4.PubMedCrossRefGoogle Scholar
  36. 36.
    Serhan CN. Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev Immunol. 2007;25:101–37.PubMedCrossRefGoogle Scholar
  37. 37.
    Amano H, Morimoto K, Senba M, Wang H, Ishida Y, Kumatori A, Yoshimine H, Oishi K, Mukaida N, Nagatake T. Essential contribution of monocyte chemoattractant protein-1/CC chemokine ligand-2 to resolution and repair processes in acute bacterial pneumonia. J Immunol. 2004;172:398–409.PubMedCrossRefGoogle Scholar
  38. 38.
    Peluso J, LaForge KS, Matthes HW, Kreek MJ, Kieffer BL, Gavériaux-Ruff C. Distribution of nociceptin/orphanin FQ receptor transcript in human central nervous system and immune cells. J Neuroimmunol. 1998;81:184–92.PubMedCrossRefGoogle Scholar
  39. 39.
    Strauss-Ayali D, Conrad SM, Mosser DM. Monocyte subpopulations and their differentiation patterns during infection. J Leukoc Biol. 2007;82:244–52.PubMedCrossRefGoogle Scholar
  40. 40.
    Warren HS. Editorial: control issues in sepsis: what modulates apoptosis? J Leukoc Biol. 2011;89:325–6.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Buzas B, Rosenberger J, Kim KW, Cox BM. Inflammatory mediators increase the expression of nociceptin/orphanin FQ in rat astrocytes in culture. Glia. 2002;39:237–46.PubMedCrossRefGoogle Scholar
  42. 42.
    Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519–50.PubMedCrossRefGoogle Scholar
  43. 43.
    Zhao H, Wu G-C, Cao X-D. Immunomodulatory activity of orphanin FQ/nociceptin on traumatic rats. Acta Pharmacol Sin. 2002;23:343.PubMedGoogle Scholar
  44. 44.
    Goldfarb Y, Reinscheid RK, Kusnecov AW. Orphanin FQ/nociceptin interactions with the immune system in vivo: gene expression changes in lymphoid organs and regulation of the cytokine response to staphylococcal enterotoxin A. J Neuroimmunol. 2006;176:76–85.PubMedCrossRefGoogle Scholar
  45. 45.
    Carvalho D, Petronilho F, Vuolo F, Machado RA, Constantino L, Guerrini R, Calo G, Gavioli EC, Streck EL, Dal-Pizzol F. The nociceptin/orphanin FQ-NOP receptor antagonist effects on an animal model of sepsis. Intensive Care Med. 2008;34:2284–90.PubMedCrossRefGoogle Scholar
  46. 46.
    Kaminsky DE, Rogers TJ. Suppression of CCL2/MCP-1 and CCL5/RANTES expression by nociceptin in human monocytes. J Neuroimmune Pharmacol. 2008;3:75–82.PubMedCrossRefGoogle Scholar
  47. 47.
    Al-Hashimi M, Scott S, Thompson J, Lambert D. Opioids and immune modulation: more questions than answers. Br J Anaesth. 2013;111:80–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348:138–50.PubMedCrossRefGoogle Scholar
  49. 49.
    Németh J, Helyes Z, Oroszi G, Thán M, Pintér E, Szolcsányi J. Inhibition of nociceptin on sensory neuropeptide release and mast cell-mediated plasma extravasation in rats. Eur J Pharmacol. 1998;347:101–4.PubMedCrossRefGoogle Scholar
  50. 50.
    Helyes Z, Németh J, Pintér E, Szolcsányi J. Inhibition by nociceptin of neurogenic inflammation and the release of SP and CGRP from sensory nerve terminals. Br J Pharmacol. 1997;121:613–5.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Petrella C, Giuli C, Broccardo M, Eutamene H, Cartier C, Leveque M, Bedini A, Spampinato S, Bueno L, Theodorou V, Improta G, Agostini S. Protective and worsening peripheral nociceptin/orphanin FQ receptor-mediated effect in a rat model of experimental colitis. Pharmacol Res. 2013;70:72–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Kapusta DR. Neurohumoral effects of orphanin FQ/nociceptin: relevance to cardiovascular and renal function. Peptides. 2000;21:1081–99.PubMedCrossRefGoogle Scholar
  53. 53.
    Hashiba E, Hirota K, Kudo T, Guerrini R, Matsuki A. Effects of nociceptin/orphanin FQ receptor ligands on blood pressure, heart rate, and plasma catecholamine concentrations in guinea pigs. Naunyn Schmiedebergs Arch Pharmacol. 2003;367:342–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Madeddu P, Salis MB, Milia AF, Emanueli C, Guerrini R, Regoli D, Calò G. Cardiovascular effects of nociceptin in unanesthetized mice. Hypertension. 1999;33:914–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Neal CR Jr, Akil H, Watson SJ Jr. Expression of orphanin FQ and the opioid receptor-like (ORL1) receptor in the developing human and rat brain. J Chem Neuroanat. 2002;22:219–49.CrossRefGoogle Scholar
  56. 56.
    Burmeister MA, Kapusta DR. 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. 2007;322:324–331.PubMedCrossRefGoogle Scholar
  57. 57.
    Burmeister MA, Ansonoff MA, Pintar JE, Kapusta DR. Nociceptin/orphanin FQ (N/OFQ)-evoked bradycardia, hypotension, and diuresis are absent in N/OFQ peptide (NOP) receptor knockout mice. J Pharmacol Exp Ther. 2008;326:897–904.PubMedCrossRefGoogle Scholar
  58. 58.
    Chu X, Xu N, Li P, Mao L, Wang JQ. Inhibition of cardiovascular activity following microinjection of novel opioid-like neuropeptide nociceptin (orphanin FQ) into the rat rostral ventrolateral medulla. Brain Res. 1999;829:134–42.PubMedCrossRefGoogle Scholar
  59. 59.
    Laufenberg LJ, Weller GE, Lang CH, Ruiz-Velasco V. Nociceptin receptor signaling in sympathetic neurons from septic rats. J Surg Res. 2013;184:973–980.Google Scholar
  60. 60.
    Stamer UM, Book M, Comos C, Zhang L, Nauck F, Stuber F. Expression of the nociceptin precursor and nociceptin receptor is modulated in cancer and septic patients. Br J Anaesth. 2011;106:566–72.PubMedCrossRefGoogle Scholar
  61. 61.
    Zhang L, Stuber F, Stamer UM. Inflammatory mediators influence the expression of nociceptin and its receptor in human whole blood cultures. PLoS One. 2013;8:e74138.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Japanese Society of Anesthesiologists 2014

Authors and Affiliations

  • Róisín Thomas
    • 1
  • Cordula Stover
    • 2
  • David G. Lambert
    • 1
  • Jonathan P. Thompson
    • 1
  1. 1.University Department of Cardiovascular Sciences, Division of Anaesthesia, Critical Care and Pain ManagementUniversity of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal InfirmaryLeicesterUK
  2. 2.Department of Infection, Immunity and Inflammation, Maurice Shock Medical Sciences BuildingUniversity of LeicesterLeicesterUK

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