The micro-opioid (beta-endorphin/micro-opioid receptor) and kappa-opioid (dynorphin A (DynA)/kappa-opioid receptor) systems play pivotal roles in the modulation of pruritus in the central nervous system. The micro-opioid system has also been identified in human epidermis, raising the possibility that the system controls the peripheral itch. However, the precise distribution of the kappa-opioid system has not yet been clarified in human epidermis. To address this issue, reverse transcription-PCR and immunohistochemical analyses were performed on cultured keratinocytes and normal skins from humans. The analyses revealed that epidermal keratinocytes express kappa-opioid receptor and its ligands, DynA (1-17) and DynA (1-8). Moreover, expression for micro- and kappa-opioid systems was examined immunohistochemically in skin biopsies from healthy volunteers and patients with atopic dermatitis (AD) before and after psoralen-ultraviolet A (PUVA) therapy. Our expression analyses showed that only the kappa-opioid system, not the micro-opioid system, was downregulated in the epidermis of AD patients. The downregulation of the micro-opioid system and the restoration of the kappa-opioid system by PUVA therapy were observed in the AD patients, concomitant with a decrease of VAS (visual analogue scale) scores. These results suggest epidermal opioid systems are associated with the modulation of pruritus in AD. This new finding may help us to understand the control mechanism of peripheral itch.