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Histamine receptor inhibitors can ameliorate itching induced by histamine, but are ineffective against other types of pruritus, such as itching of atopic dermatitis (AD) patients. Also, magnetic resonance imaging (fMRI) has shown that histamine-induced itching and acute itching in AD activate different areas of the brain. Thus, the mechanisms of histamine-induced itching and itching of AD patents appear to be different. It has been reported that the number of nerve fibers in the epidermis of AD patients is significantly higher than that in healthy controls, and so it was suggested that elongation and increase of nerve fibers in the epidermis cause the itching in AD patients. However, we recently quantified the three-dimensional structures of nerve fibers in back skin from healthy subjects and AD patients by means of two-photon microscopy. We found that although nerve fibers extended further from the basal membrane of epidermis in AD patients than in healthy subjects, the density of nerve fibers in epidermis was significantly lower in AD patients. Also, the number of fibers passing through the basal membrane was lower in AD than in healthy subjects. Thus, we concluded that the mechanism of itching in AD patients was independent of nerve fiber density in the epidermis. Recently, a new mechanism of histamine-independent itching was proposed, triggered by protease-activated receptor 2 (PAR2) in keratinocytes. In this connection, we recently demonstrated that Japanese Cedar pollen allergen induces elevation of intracellular calcium in human keratinocytes via PAR2 and impairs the epidermal barrier function of human skin ex vivo. Thus, certain allergens might induce both deterioration of epidermal permeability barrier homeostasis and histamine-independent itching.
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