LAUSR

Tacrolimus ointment (FK506), a calcineurin inhibitor, is a widely used topical medication in atopic dermatitis (AD) [1]. Although it is effective, pruritus and stinging sensation are common, particularly in AD patients [1]. Mediators of mast cells such as histamine have been suggested to be involved in the pathogenesis of tacrolimus-related pruritus by binding to the corresponding receptors on sensory nerve fibers [2]. Histamine acts on histamine receptors (HR) and activates the downstream transduction channel transient receptor potential V1 (TRPV1), which induces histamine-dependent pruritus [3]. It has been shown that FK506 application on inflamed skin may activate nociceptive C-fibers, which bear bradykinin receptors and capsaicin-sensitive heat transducer of TRPV1 [4]. It may lead dorsal root ganglion (DRG) depolarization and release of the neuropeptides such as substance P (SP) and CGRP of murine skin [2], that may be responsible for tacrolimus-related side effects, including pruritus [4]. The precise underlying mechanism of tacrolimus-induced pruritus, however, remains unknown. To evaluate the influence of tacrolimus on pruritus, we used an oxazolone-induced chronic contact hypersensitivity (CHS) murine model (see Supplemental Information) that produces a characteristic barrier abnormality, epidermal change and chronic T helper (Th)2-like hypersensitivity reaction with other multiple features of human AD; therefore, this model has been considered as an animal model of AD [5]. 20 mg of tacrolimus (0.1%) ointment was applied daily for 25 consecutive days following the day of sixth oxazolone ear painting. Ear inflammation and ear swelling were significantly decreased in the tacrolimus-treated group (Fig.1a and b). However, the scratching counts were significantly increased in tacrolimustreated group (Fig. 1c). To examine whether the scratching behavior is provoked by the irritating effect of topical ointment, we applied 20 mg of tacrolimus (0.1%) ointment to the ears of wild-type mice (BALB/c mice) for one