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


METHODS
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).


METHODS
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.
Department of Pharmacology and Pharmacotherapy, University of Pécs, Pécs, Hungary.
István
I
Szitter
Erika
E
Pintér
Anikó
A
Perkecz
Agnes
A
Kemény
József
J
Kun
László
L
Kereskai
Claudio
C
Pietra
John P
JP
Quinn
Andreas
A
Zimmer
Alexandra
A
Berger
Christopher J
CJ
Paige
Zsuzsanna
Z
Helyes
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003106:Colon / Q000473:pathology; D016207:Cytokines / Q000032:analysis; D016264:Dextran Sulfate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064729:Neurokinin-1 Receptor Antagonists / Q000627:therapeutic use*; D009195:Peroxidase / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000502:physiology*; D012720:Severity of Illness Index; D010879:Piperazines; D044482:Benzeneacetamides
D016207:Cytokines; D016264:Dextran Sulfate; D064729:Neurokinin-1 Receptor Antagonists; D009195:Peroxidase; D011725:Pyridines; D018040:Receptors, Neurokinin-1; C508854:netupitant; D010879:Piperazines; D044482:Benzeneacetamides