title: Superoxide generation and leukocyte accumulation: key elements in the mediation of leukotriene B₄-induced itch by transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1.
abstract: The underlying mechanisms of itch are poorly understood. We have investigated a model involving the chemoattractant leukotriene B₄ (LTB₄) that is up-regulated in common skin diseases. Intradermal injection of LTB4 (0.1 nmol/site) into female CD1 mice induced significant scratching movements (used as an itch index) compared with vehicle-injected (0.1% bovine serum albumin-saline) mice. Intraperitoneal transient receptor potential (TRP) channel antagonist treatment significantly inhibited itch as follows: TRP vanilloid 1 (TRPV1) antagonist SB366791 (0.5 mg/kg, by 97%) and the TRP ankyrin 1 (TRPA1) antagonists TCS 5861528 (10 mg/kg; 82%) and HC-030031 (100 mg/kg; 76%). Leukotriene B₄ receptor 2 antagonism by LY255283 (5 mg/kg i.p.; 62%) reduced itch. Neither TRPV1-knockout (TRPV1-KO) nor TRPA1-knockout (TRPA1-KO mice exhibited LTB₄-induced itch compared with their wild-type counterparts. The reactive oxygen species scavengers N-acetylcysteine (NAC; 204 mg/kg i.p.; 86%) or superoxide dismutase (SOD; 10 mg/kg i.p.; 83%) also inhibited itch. LTB4-induced superoxide release was attenuated by TCS 5861528 (56%) and HC-030031 (66%), NAC (58%), SOD (50%), and LY255283 (59%) but not by the leukotriene B4 receptor 1 antagonist U-75302 (9 nmol/site) or SB366791. Itch, superoxide, and myeloperoxidase generation were inhibited by the leukocyte migration inhibitor fucoidan (10 mg/kg i.v.) by 80, 61, and 34%, respectively. Myeloperoxidase activity was also reduced by SB366791 (35%) and SOD (28%). TRPV1-KO mice showed impaired myeloperoxidase release, whereas TRPA1-KO mice exhibited diminished production of superoxide. This result provides novel evidence that TRPA1 and TRPV1 contribute to itch via distinct mechanisms.
authors.affiliation: Programa de Pós-Graduação em Biologia Parasitária, Universidade Ceuma, São Luís, Brazil.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Fernandes
authors.forename: Chi Teng
authors.initials: CT
authors.lastname: Vong
authors.forename: Samuel
authors.initials: S
authors.lastname: Quek
authors.forename: Jessica
authors.initials: J
authors.lastname: Cheong
authors.forename: Salma
authors.initials: S
authors.lastname: Awal
authors.forename: Clive
authors.initials: C
authors.lastname: Gentry
authors.forename: Aisah A
authors.initials: AA
authors.lastname: Aubdool
authors.forename: Lihuan
authors.initials: L
authors.lastname: Liang
authors.forename: Jennifer V
authors.initials: JV
authors.lastname: Bodkin
authors.forename: Stuart
authors.initials: S
authors.lastname: Bevan
authors.forename: Richard
authors.initials: R
authors.lastname: Heads
authors.forename: Susan D
authors.initials: SD
authors.lastname: Brain
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000494:pharmacology; D005260:Female; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D007975:Leukotriene B4 / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D011537:Pruritus / Q000188:drug therapy / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors; D013481:Superoxides / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
chemical_list: D017487:Ankyrins; D018102:Receptors, Leukotriene B4; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D050051:Transient Receptor Potential Channels; D013481:Superoxides; D007975:Leukotriene B4