Evidence for the role of neurogenic inflammation components in trypsin-elicited scratching behaviour in mice.
OBJECTIVE
We investigated the mechanisms underlying the pruritogenic response induced by trypsin in mice, to assess the relevance of neurogenic inflammation components in this response.


METHODS
Itching was induced by an intradermal injection of trypsin in the mouse neck. The animals were observed for 40 min and their scratching behaviour was quantified.


RESULTS
Trypsin-induced itching was blocked by the lima bean trypsin inhibitor, the selective proteinase-activated receptor-2 (PAR-2) antagonist FSLLRY and PAR-2 receptor desensitization. An important involvement of mast cells was observed, as chronic pretreatment with the mast cell degranulator compound 48/80 or the mast cell stabilizer disodium cromoglycate prevented scratching. Also, trypsin response was inhibited by the selective COX-2 inhibitor celecoxib and by the selective kinin B2 (FR173657) and B1 (SSR240612) receptor antagonists. Moreover, an essential role for the mediators of neurogenic inflammation was established, as the selective NK1 (FK888), NK3 (SR142801) and calcitonin gene-related peptide (CGRP(8-37) fragment) receptor antagonists inhibited trypsin-induced itching. Similarly, blockade of transient receptor potential vanilloid 1 (TRPV1) receptors by the selective TRPV1 receptor antagonist SB366791, or by genetic deletion of TRPV1 receptor reduced this behaviour in mice. C-fibre desensitization showed a very similar result.


CONCLUSIONS
Trypsin intradermal injection proved to be a reproducible model for the study of itching and the involvement of PAR-2 receptors. Also, trypsin-induced itching seems to be widely dependent on neurogenic inflammation, with a role for TRPV1 receptors. In addition, several other mediators located in the sensory nerves and skin also seem to contribute to this process.
Costa
R
R
Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
Marotta
D M
DM
Manjavachi
M N
MN
Fernandes
E S
ES
Lima-Garcia
J F
JF
Paszcuk
A F
AF
Quintão
N L M
NL
Juliano
L
L
Brain
S D
SD
Calixto
J B
JB
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000982:Antipruritics / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D065168:Bradykinin Receptor Antagonists; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D000068579:Celecoxib; D015550:Cell Degranulation / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology; D004205:Cromolyn Sodium / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology; D004195:Disease Models, Animal; D007271:Injections, Intradermal; D008297:Male; D008407:Mast Cells / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D036421:Nerve Fibers, Unmyelinated / Q000378:metabolism; D020078:Neurogenic Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010940:Plant Proteins / Q000494:pharmacology; D011537:Pruritus / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D011720:Pyrazoles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018002:Receptors, Bradykinin / Q000378:metabolism; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014357:Trypsin / Q000008:administration & dosage; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
C487113:2-((3-(1,3-benzodioxol-5-yl)-3-(((6-methoxy-2-naphthyl)sulfonyl)amino)propanoyl)amino)-3-(4-((2,6-dimethylpiperidinyl)methyl)phenyl)-N-isopropyl-N-methylpropanamide; D000813:Anilides; D000982:Antipruritics; D065168:Bradykinin Receptor Antagonists; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002934:Cinnamates; D052246:Cyclooxygenase 2 Inhibitors; D004149:Dioxoles; C105311:FR 173657; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D009842:Oligopeptides; D010446:Peptide Fragments; D010940:Plant Proteins; D011720:Pyrazoles; D011804:Quinolines; D044464:Receptor, PAR-2; D018002:Receptors, Bradykinin; D018015:Receptors, Calcitonin Gene-Related Peptide; D013449:Sulfonamides; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C025398:protease inhibitor protein, Phaseolus lunatus; C058636:calcitonin gene-related peptide (8-37); D003189:p-Methoxy-N-methylphenethylamine; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D014357:Trypsin; D000068579:Celecoxib; D015740:Calcitonin Gene-Related Peptide; D004205:Cromolyn Sodium