title: Repeated topical application of glucocorticoids augments irritant chemical-triggered scratching in mice.
abstract: Topical glucocorticoids, widely used for the treatment of a variety of dermatitises, are known to exacerbate atopic dermatitis after long-term or inappropriate use. In some animal models, topical glucocorticoids augment the allergic cutaneous inflammation after repeated application, suggesting a relationship between these and clinical observations. We investigated whether topical glucocorticoids augment itching, rather than inflammation, resulting in the exacerbation of atopic dermatitis. Mice receiving repeated topical application of glucocorticoids, betamethasone valerate or dexamethasone, to the ear for 1 week showed significantly higher scratching frequency after application of an irritant chemical, 2,4-dinitrofluorobenzene (DNFB) or 12-O-tetradecanoilphorbol 13-acetate (TPA) than those receiving either a glucocorticoid or irritant chemical alone. In contrast, the increase in ear thickness induced by application of TPA was significantly suppressed by dexamethasone. Substance P (SP) and nerve growth factor (NGF) levels were higher in the ear receiving betamethasone valerate followed by DNFB application than in that receiving DNFB alone. In addition, histopathological studies revealed an increased density of nerve fibers in the ear receiving betamethasone valerate or dexamethasone followed by DNFB application. Oral administration of betamethasone valerate was not associated with an increase in either scratching frequency or SP or NGF level in the ear. These results suggest that repeated topical application of glucocorticoids may augment irritant chemical-triggered scratching through an increase in SP and NGF levels and nerve fiber density at the application site. These findings might explain the etiology of the exacerbation of atopic dermatitis and other dermatitises, occurring after long-term or inappropriate use of topical glucocorticoids.
authors.affiliation: Applied Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharmaceutical Inc, Tsukuba, Ibaraki, Japan. yasutomo.fujii@jp.astellas.com
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Fujii
authors.forename: Takanori
authors.initials: T
authors.lastname: Sengoku
authors.forename: Shoji
authors.initials: S
authors.lastname: Takakura
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001624:Betamethasone Valerate / Q000008:administration & dosage; D003876:Dermatitis, Atopic / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology*; D017453:Dermatitis, Irritant / Q000150:complications* / Q000209:etiology* / Q000503:physiopathology; D003907:Dexamethasone / Q000008:administration & dosage; D004139:Dinitrofluorobenzene / Q000008:administration & dosage; D004195:Disease Models, Animal; D018450:Disease Progression; D004431:Ear, External / Q000187:drug effects; D005938:Glucocorticoids / Q000009:adverse effects* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D010703:Phorbol Esters / Q000008:administration & dosage; D023422:Skin Irritancy Tests
chemical_list: D005938:Glucocorticoids; D010703:Phorbol Esters; D003907:Dexamethasone; D001624:Betamethasone Valerate; D004139:Dinitrofluorobenzene