Histamine H4 receptor antagonism reduces hapten-induced scratching behaviour but not inflammation.
Effects of the histamine H(4) receptor antagonist JNJ 7777120 (1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine) were tested in two models of allergic contact dermatitis. Dermatitis was induced by 2,4-dinitrochlorobenzene and toluene-2,4-diisocyanate, which differ in their Th1-Th2 profile in that way that 2,4-dinitrochlorobenzene is a classical contact allergen with a pronounced Th1-mediated inflammation, while the respiratory chemical allergen toluene-2,4-diisocyanate induces a Th2-dominated inflammation. JNJ 7777120 (15 mg/kg) administered 2 h and 30 min before and 1 h after challenge did not reduce the hapten-induced ear swelling determined 24 h after challenge. This was confirmed by histological evaluation of the ear skin. A repeated administration of the haptens to the rostral part of the back of sensitized animals resulted in a frequent scratching behaviour. An administration of JNJ 7777120 (15 mg/kg) 30 min before challenge reduced this hapten-induced scratching significantly. The H(1) receptor antagonist cetirizine also reduced the scratching bouts in sensitized mice. A combination of H(1) and H(4) receptor antagonists resulted in the strongest inhibition of scratching behaviour associated with allergic dermatitis. These results indicate that H(4) receptor antagonism fails to reduce the allergic inflammatory response but strongly inhibits allergen-induced itch. Thus, a combination of H(4) and H(1) receptor antagonism might be a new strategy to treat pruritus related to allergic diseases like atopic dermatitis.
Rossbach
Kristine
K
Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
Wendorff
Stephanie
S
Sander
Kerstin
K
Stark
Holger
H
Gutzmer
Ralf
R
Werfel
Thomas
T
Kietzmann
Manfred
M
Bäumer
Wolfgang
W
D000818:Animals; D003876:Dermatitis, Atopic; D004305:Dose-Response Relationship, Drug; D005260:Female; D006241:Haptens / Q000737:chemistry*; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D007249:Inflammation; D051379:Mice; D008807:Mice, Inbred BALB C; D010879:Piperazines / Q000494:pharmacology*; D011537:Pruritus / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D018418:Th2 Cells / Q000276:immunology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
C418607:HRH4 protein, human; D006241:Haptens; D006634:Histamine H1 Antagonists; D007093:Imidazoles; D007211:Indoles; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D013890:Thiourea; C086108:clobenpropit