Inflammation Research

, Volume 63, Issue 5, pp 399–409

Role of neurokinin 1 receptors in dextran sulfate-induced colitis: studies with gene-deleted mice and the selective receptor antagonist netupitant

  • István Szitter
  • Erika Pintér
  • Anikó Perkecz
  • Ágnes Kemény
  • József Kun
  • László Kereskai
  • Claudio Pietra
  • John P. Quinn
  • Andreas Zimmer
  • Alexandra Berger
  • Christopher J. Paige
  • Zsuzsanna Helyes
Original Research Paper

Abstract

Objective and design

The function of the neurokinin 1 (NK1) receptor was investigated in the DSS-induced mouse colitis model using NK1 receptor-deficient mice and the selective antagonist netupitant.

Subjects

Colitis was induced by oral administration of 20 mg/ml DSS solution for 7 days in C57BL/6 and Tacr1 KO animals (n = 5–7).

Treatment

During the induction, one-half of the C57BL/6 and Tacr1 KO group received one daily dose of 6 mg/kg netupitant, administered intraperitoneally, the other half of the group received saline, respectively.

Methods

Disease activity index (DAI), on the basis of stool consistency, blood and weight loss, was determined over 7 days. Histological evaluation, myeloperoxidase (MPO) measurement, cytokine concentrations and receptor expression analysis were performed on the colon samples.

Results

NK1 receptors are up-regulated in the colon in response to DSS treatment. DSS increased DAI, histopathological scores, BLC, sICAM-1, IFN-γ, IL-16 and JE in wildtype mice, which were significantly reduced in NK1 receptor-deficient ones. NK1 receptor antagonism with netupitant significantly diminished DAI, inflammatory histopathological alterations, BLC, IFN-γ, IL-13 and IL-16 in wildtype mice, but not in the NK1-deficient ones. MPO was similarly elevated and netupitant significantly decreased its activity in both groups.

Conclusions

NK1 receptor antagonism could be beneficial for colitis via inhibiting different inflammatory mechanisms.

Keywords

Neurogenic inflammation Tachykinins Inflammatory bowel disease Edema NK1 receptor antagonist 

References

  1. 1.
    Yamamoto H, Morise K, Kusugami K, Furusawa A, Konagaya T, Nishio Y, et al. Abnormal neuropeptide concentration in rectal mucosa of patients with inflammatory bowel disease. J Gastroenterol. 1996;31:525–32.PubMedCrossRefGoogle Scholar
  2. 2.
    Gross KJ, Pothoulakis C. Role of neuropeptides in inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:918–32.PubMedCrossRefGoogle Scholar
  3. 3.
    Keränen U, Kiviluoto T, Järvinen H, Bäck N, Kivilaakso E, Soinila S. Changes in substance P-immunoreactive innervation of human colon associated with ulcerative colitis. Dig Dis Sci. 1995;40:2250–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Zhang Y, Lu L, Furlonger C, Wu GE, Paige CJ. Hemokinin is a hematopoietic-specific tachykinin that regulates B lymphopoiesis. Nat Immunol. 2000;1:392–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Zhang Y, Paige CJ. T-cell developmental blockage by tachykinin antagonists and the role of hemokinin 1 in T lymphopoiesis. Blood. 2003;102:2165–72.PubMedCrossRefGoogle Scholar
  6. 6.
    Page NM. Hemokinins and endokinins. Cell Mol Life Sci. 2004;61:1652–63.PubMedCrossRefGoogle Scholar
  7. 7.
    Page NM. New challenges in the study of the mammalian tachykinins. Peptides. 2005;26:1356–68.PubMedCrossRefGoogle Scholar
  8. 8.
    Bernstein CN, Robert ME, Eysselein VE. Rectal substance P concentrations are increased in ulcerative colitis but not in Crohn’s disease. Am J Gastroenterol. 1993;88:908–13.PubMedGoogle Scholar
  9. 9.
    Michalski CW, Autschbach F, Selvaggi F, Shi X, Di Mola FF, Roggo A, et al. Increase in substance P precursor mRNA in noninflamed small-bowel sections in patients with Crohn’s disease. Am J Surg. 2007;193:476–81.PubMedCrossRefGoogle Scholar
  10. 10.
    Renzi D, Mantellini P, Calabrò A, Panerai C, Amorosi A, Paladini I, et al. Substance P and vasoactive intestinal polypeptide but not calcitonin gene-related peptide concentrations are reduced in patients with moderate and severe ulcerative colitis. Ital J Gastroenterol Hepatol. 1998;30:62–70.PubMedGoogle Scholar
  11. 11.
    Goode T, O’Connell J, Anton P, Wong H, Reeve J, O’Sullivan GC, et al. Neurokinin-1 receptor expression in inflammatory bowel disease: molecular quantitation and localisation. Gut. 2000;47:387–96.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Cutrufo C, Evangelista S, Cirillo R, Ciucci A, Conte B, Lopez G, et al. Protective effect of the tachykinin NK2 receptor antagonist nepadutant in acute rectocolitis induced by diluted acetic acid in guinea-pigs. Neuropeptides. 2000;34:355–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Stucchi AF, Shofer S, Leeman S, Materne O, Beer E, McClung J, et al. NK-1 antagonist reduces colonic inflammation and oxidative stress in dextran sulfate-induced colitis in rats. Am J Physiol Gastrointest Liver Physiol. 2000;279:G1298–306.PubMedGoogle Scholar
  14. 14.
    Rijnierse A, van Zijl K, Koster A. Beneficial effect of tachykinin NK 1 receptor antagonism in the development of hapten-induced colitis in mice. Eur J Pharmacol. 2006;548:150–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Ursino MG, Vasina V, De Ponti F. Protection from DNBS-induced colitis by the tachykinin NK(1) receptor antagonist SR140333 in rats. Eur J Pharmacol. 2009;603:133–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Mazelin L, Theodorou V, More J, Emonds-Alt X, Fioramonti J, Bueno L, et al. Comparative effects of nonpeptide tachykinin receptor agonists on experimental gut inflammation in rats and guinea-pigs. Tachykin Gut Inflamm. 1998;63:293–304.Google Scholar
  17. 17.
    Improta G, Carpino F, Petrozza V, Guglietta A, Tabacco A, Broccardo M. Central effects of selective NK 1 and NK 3 tachykinin receptor agonists on two models of experimentally-induced colitis in rats. Peptides. 2003;24:903–11.PubMedCrossRefGoogle Scholar
  18. 18.
    Engel MA, Khalil M, Mueller-Tribbensee SM, Becker C, Neuhuber WL, Neurath MF, et al. The proximodistal aggravation of colitis depends on substance P released from TRPV1-expressing sensory neurons. J Gastroenterol. 2012;47:256–65.PubMedCrossRefGoogle Scholar
  19. 19.
    Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology. 1990;98:694–702.PubMedGoogle Scholar
  20. 20.
    Morris GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL. Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology. 1989;96:795–803.PubMedGoogle Scholar
  21. 21.
    Rees V, Dieleman LA, Palmen MJHJ, Akol H, Bloemena E, Pena SGMM AS. Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines. Clin Exp Immunol. 2001;2:385–91.Google Scholar
  22. 22.
    Yan Y, Kolachala V, Dalmasso G, Nguyen H, Laroui H, Sitaraman SV, et al. Temporal and spatial analysis of clinical and molecular parameters in dextran sodium sulfate induced colitis. PLoS ONE. 2009;4:e6073.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Egger B, Thomas B-E, Macdonald T. Characterisation of acute murine dextran sodium sulphate colitis: cytokine profile and dose dependency. Digestion. 2000;62(4):240–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Scheiffele F, Fuss IJ (2002) Induction of TNBS colitis in mice. Curr. Protoc. Immunol. Chapter 15:Unit 15.19.Google Scholar
  25. 25.
    Rizzi A, Campi B, Camarda V, Molinari S, Cantoreggi S, Regoli D, et al. In vitro and in vivo pharmacological characterization of the novel NK1 receptor selective antagonist Netupitant. Peptides. 2012;37:86–97.PubMedCrossRefGoogle Scholar
  26. 26.
    Zimmer A, Zimmer AM, Baffi J, Usdin T, Reynolds K, König M, et al. Hypoalgesia in mice with a targeted deletion of the tachykinin 1 gene. Proc Natl Acad Sci USA. 1998;95:2630–5.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    De Felipe C, Herrero JF, O’Brien JA, Palmer JA, Doyle CA, Smith AJ, et al. Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature. 1998;392:394–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Laird JM, Olivar T, Roza C, De Felipe C, Hunt SP, Cervero F. Deficits in visceral pain and hyperalgesia of mice with a disruption of the tachykinin NK1 receptor gene. Neuroscience. 2000;98:345–52.PubMedCrossRefGoogle Scholar
  29. 29.
    Helyes Z, Szabó A, Németh J, Jakab B, Pintér E, Bánvölgyi A, et al. Antiinflammatory and analgesic effects of somatostatin released from capsaicin-sensitive sensory nerve terminals in a Freund’s adjuvant-induced chronic arthritis model in the rat. Arthr Rheum. 2004;50:1677–85.CrossRefGoogle Scholar
  30. 30.
    Szitter I, Pozsgai G, Sandor K, Elekes K, Kemeny A, Perkecz A, et al. The role of transient receptor potential vanilloid 1 (TRPV1) receptors in dextran sulfate-induced colitis in mice. J Mol Neurosci. 2010;42:80–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Kihara N, de la Fuente SG, Fujino K, Takahashi T, Pappas TN, Mantyh CR. Vanilloid receptor-1 containing primary sensory neurones mediate dextran sulphate sodium induced colitis in rats. Gut. 2003;52:713–9.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Von Euler US, Gaddum JH. An unidentified depressor substance in certain tissue extracts. J Physiol. 1931;72(1):74–86.Google Scholar
  33. 33.
    Kimura S. Novel neuropeptides, neurokinins A and B, isolated from porcine spinal cord. Proc Jpn Acad Ser. 1983;5:101–4.CrossRefGoogle Scholar
  34. 34.
    Nawa H, Doteuchi M, Igano K, Inouye K, Nakanishi S. Substance K: a novel mammalian tachykinin that differs from substance P in its pharmacological profile. Life Sci. 1984;34:1153–60.PubMedCrossRefGoogle Scholar
  35. 35.
    Tatemoto K, Lundberg JM, Jörnvall H, Mutt V. Neuropeptide K: isolation, structure and biological activities of a novel brain tachykinin. Biochem Biophys Res Commun. 1985;128:947–53.PubMedCrossRefGoogle Scholar
  36. 36.
    Kage R, McGregor GP, Thim L, Conlon JM. Neuropeptide-gamma: a peptide isolated from rabbit intestine that is derived from gamma-preprotachykinin. J Neurochem. 1988;50:1412–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Masu Y, Nakayama K, Tamaki H, Harada Y, Kuno M, Nakanishi S. cDNA cloning of bovine substance-K receptor through oocyte expression system. Nature. 1987;329:836–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Yokota Y, Sasai Y, Tanaka K, Fujiwara T, Tsuchida K, Shigemoto R, et al. Molecular characterization of a functional cDNA for rat substance P receptor. J Biol Chem. 1989;264:17649–52.PubMedGoogle Scholar
  39. 39.
    Biolow M, Shigemoto R, Yokota Y, Tsuchida K, Nakanishi S. Cloning and expression of a rat neuromedin K receptor cDNA. J Biol Chem. 1990;265:623–8.Google Scholar
  40. 40.
    Daoui S, Cui YY, Lagente V, Emonds-Alt X, Advenier C. A tachykinin NK3 receptor antagonist, SR 142801 (osanetant), prevents substance P-induced bronchial hyperreactivity in guinea-pigs. Pulm Pharmacol Ther. 1997;10:261–70.PubMedCrossRefGoogle Scholar
  41. 41.
    Muñoz M, Rosso M. The NK-1 receptor antagonist aprepitant as a broad spectrum antitumor drug. Inv New Drugs. 2010;28:187–93.CrossRefGoogle Scholar
  42. 42.
    Koon HW, Pothoulakis C. Immunomodulatory properties of substance P: the gastrointestinal system as a model. Ann N Y Acad Sci. 2006;1088:23–40.PubMedCrossRefGoogle Scholar
  43. 43.
    Barthó L, Holzer P. Search for a physiological role of substance P in gastrointestinal motility. Neuroscience. 1985;16:1–32.PubMedCrossRefGoogle Scholar
  44. 44.
    Holzer P, Lippe IT, Heinemann A, Barthó L. Tachykinin NK1 and NK2 receptor-mediated control of peristaltic propulsion in the guinea-pig small intestine in vitro. Neuropharmacology. 1998;37:131–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Lecci A, De Giorgio R, Barthó L, Sternini C, Tramontana M, Corinaldesi R, et al. Tachykinin NK(1)receptor-mediated inhibitory responses in the guinea-pig small intestine. Neuropeptides. 1999;33:91–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Stewart JP, Kipar A, Cox H, Payne C, Vasiliou S, Quinn JP. Induction of tachykinin production in airway epithelia in response to viral infection. PLoS ONE. 2008;3:e1673.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Maggi CA, Patacchini R, Rovero P, Giachetti A. Tachykinin receptors and tachykinin receptor antagonists. J Auton Pharmacol. 1993;13:23–93.PubMedCrossRefGoogle Scholar
  48. 48.
    Burcher E, Watkins DJ, O’Flynn NM. Both neurokinin A and substance P bind to NK1 receptors in guinea-pig lung. Pulm Pharmacol. 1989;1:201–3.PubMedCrossRefGoogle Scholar
  49. 49.
    Otsuka M, Yoshioka K. Neurotransmitter functions of mammalian tachykinins. Physiol Rev. 1993;73:229–308.PubMedGoogle Scholar
  50. 50.
    Petitet F, Saffroy M, Torrens Y, Lavielle S, Chassaing G, Loeuillet D, et al. Possible existence of a new tachykinin receptor subtype in the guinea pig ileum. Peptides. 1992;13:383–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Maggi CA, Schwartz TW. The dual nature of the tachykinin NK1 receptor. Tren Pharmacol Sci. 1997;18:351–5.CrossRefGoogle Scholar
  52. 52.
    Alvaro G, Di Fabio R. Neurokinin 1 receptor antagonists––current prospects. Curr Opin Drug Discov Devel. 2007;10:613–21.PubMedGoogle Scholar
  53. 53.
    Holzer P, Holzer-Petsche U. Tachykinin receptors in the gut: physiological and pathological implications. Curr Opin Pharmacol. 2001;1:583–90.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  • István Szitter
    • 1
    • 2
  • Erika Pintér
    • 1
    • 2
    • 3
  • Anikó Perkecz
    • 1
    • 2
  • Ágnes Kemény
    • 1
    • 2
  • József Kun
    • 1
    • 2
  • László Kereskai
    • 4
  • Claudio Pietra
    • 5
  • John P. Quinn
    • 6
  • Andreas Zimmer
    • 7
  • Alexandra Berger
    • 8
    • 9
  • Christopher J. Paige
    • 8
    • 9
  • Zsuzsanna Helyes
    • 1
    • 2
    • 3
  1. 1.Department of Pharmacology and PharmacotherapyUniversity of PécsPécsHungary
  2. 2.János Szentágothai Research CentrePécsHungary
  3. 3.PharmInVivo Ltd.PécsHungary
  4. 4.Department of PathologyUniversity of PécsPécsHungary
  5. 5.Helsinn Healthcare SA, Preclinical R&DLuganoSwitzerland
  6. 6.Department of Molecular and Clinical Pharmacology, Institute of TranslationUniversity of Liverpool, Liverpool UniversityLiverpoolUK
  7. 7.Institute of Molecular PsychiatryUniversity of BonnBonnGermany
  8. 8.Ontario Cancer InstituteUniversity Health NetworkTorontoCanada
  9. 9.Department of ImmunologyUniversity of TorontoTorontoCanada

Personalised recommendations