title: Mechanisms Underlying the Scratching Behavior Induced by the Activation of Proteinase-Activated Receptor-4 in Mice.
abstract: A role for proteinase-activated receptor-4 (PAR-4) was recently suggested in itch sensation. Here, we investigated the mechanisms underlying the pruriceptive actions of the selective PAR-4 agonist AYPGKF-NH2 (AYP) in mice. Dorsal intradermal (i.d.) administration of AYP elicited intense scratching behavior in mice, which was prevented by the selective PAR-4 antagonist (pepducin P4pal-10). PAR-4 was found to be coexpressed in 32% of tryptase-positive skin mast cells, and AYP caused a 2-fold increase in mast cell degranulation. However, neither the treatment with cromolyn nor the deficiency of mast cells (WBB6F1-Kit(W/Wv) mice) was able to affect AYP-induced itch. PAR-4 was also found on gastrin-releasing peptide (GRP)-positive neurons (pruriceptive fibers), and AYP-induced itch was reduced by the selective GRP receptor antagonist RC-3095. In addition, AYP evoked calcium influx in ∼1.5% of cultured DRG neurons also sensitive to TRPV1 (capsaicin) and/or TRPA1 (AITC) agonists. Importantly, AYP-induced itch was reduced by treatment with either the selective TRPV1 (SB366791), TRPA1 (HC-030031), or NK1 (FK888) receptor antagonists. However, genetic loss of TRPV1, but not of TRPA1, diminished AYP-induced calcium influx in DRG neurons and the scratching behavior in mice. These findings provide evidence that PAR-4 activation by AYP causes pruriceptive itch in mice via a TRPV1/TRPA1-dependent mechanism.
authors.affiliation: Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
authors.forename: Eliziane S
authors.initials: ES
authors.lastname: Patricio
authors.affiliation: Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil; Department of Pharmaceutical Biotechnology, School of Pharmacy, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Robson
authors.initials: R
authors.lastname: Costa
authors.affiliation: Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil; Department of Pharmaceutical Biotechnology, School of Pharmacy, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Claudia P
authors.initials: CP
authors.lastname: Figueiredo
authors.affiliation: Wolfson Centre for Age Related Diseases, Cardiovascular Division, King's College London, London, UK.
authors.forename: Katharina
authors.initials: K
authors.lastname: Gers-Barlag
authors.affiliation: Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
authors.forename: Maíra A
authors.initials: MA
authors.lastname: Bicca
authors.affiliation: Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
authors.forename: Marianne N
authors.initials: MN
authors.lastname: Manjavachi
authors.affiliation: Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
authors.forename: Gabriela C
authors.initials: GC
authors.lastname: Segat
authors.affiliation: Wolfson Centre for Age Related Diseases, Cardiovascular Division, King's College London, London, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: Gentry
authors.affiliation: Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Luiz
authors.affiliation: Vascular Biology and Inflammation Section, Cardiovascular Division, King's College London, London, UK; Programa de Pós-Graduação, Universidade Ceuma, São Luís, Brazil.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Fernandes
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto USP.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.affiliation: Wolfson Centre for Age Related Diseases, Cardiovascular Division, King's College London, London, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Bevan
authors.affiliation: Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil. Electronic address: joao.calixto@ufsc.br.
authors.forename: João B
authors.initials: JB
authors.lastname: Calixto
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002211:Capsaicin / Q000494:pharmacology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D007150:Immunohistochemistry; D007271:Injections, Intradermal; D008407:Mast Cells / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011537:Pruritus / Q000139:chemically induced / Q000503:physiopathology* / Q000523:psychology; D011897:Random Allocation; D018004:Receptors, Bombesin / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000378:metabolism*; D012016:Reference Values; D015398:Signal Transduction; D050051:Transient Receptor Potential Channels / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018004:Receptors, Bombesin; D018179:Receptors, Thrombin; D050051:Transient Receptor Potential Channels; C112908:protease-activated receptor 4; D002211:Capsaicin