We have previously shown that human epidermal keratinocytes express a functionally active µ-opiate receptor, which adds a new dimension to the recently developed research in neuroimmunodermatology and neurogenic inflammation in skin diseases. Human keratinocytes specifically bind and also produce β-endorphin, the endogenous µ-opiate receptor ligand. Using confocal imaging microscopy, we could now demonstrate that µ-opiate receptors are not only expressed in keratinocytes, but also on unmyelinated peripheral nerve fibers in the dermis and epidermis. Some of the peripheral nerve fibers also express the ligand β-endorphin. The keratinocytes positive for β-endorphin staining are clustered around the terminal ends of the unmyelinated nerve fibers. Therefore the opiate receptor system seems to be crucial in the direct communication between nerves and skin. The keratinocytes can influence the unmyelinated nerve fibers in the epidermis directly via secreting β-endorphin. On the other hand, nerve fibers can also secrete β-endorphin and influence the migration, differentiation and probably also the cytokine production pattern of keratinocytes.

Skin biopsy specimens from 4 patients with typical acne rosacea lesions were examined for the presence of T-cell subsets using monoclonal antibodies. The infiltrates consisted chiefly of LEU-1 reactive T cells with a predominance of LEU-3a antibody positive helper-inducer T cells, while LEU-2a staining suppressor-cytotoxic T cells were scarce. These cells penetrated regularly into the follicular wall and the epidermis. The study showed that most T cells in the dermal granulomatous infiltrates around Demodex parts, which were displaced extrafoUicularly, were helper-inducer T cells. The predominance of helper-inducer T-cell subsets in the dermal infiltrates of acne rosacea lesions in frequent association with Demodex supports the hypothesis that a cell-mediated immune response plays an important role in the pathogenesis of rosacea.

It has been reported that opioid peptides modulate the differentiation of normal human keratinocytes and that mu-opiate receptors are expressed in human epidermis. The regulation of keratinocyte differentiation is particularly important in psoriasis, and one of the markers for hyperproliferative and differentiating skin diseases is cytokeratin 16. The finding that the endogenous mu-opiate receptor ligand beta-endorphin is increased in serum of patients with psoriasis indicates that the mu-opiate system may play an important role in the pathophysiology of the skin. In this study, we addressed the question whether there is a link between mu-opiate receptor regulation and cytokeratin 16 expression in normal and psoriatic skin. Firstly, we demonstrate that beta-endorphin concentrations between 16 and 1000 nM significantly downregulate mu-opiate receptor expression in epidermis of cultured human skin after 48 h. Secondly, we show that beta-endorphin regulates cytokeratin 16 expression in the epidermis of skin organ cultures exposed to 41-125 nM beta-endorphin for 48 h, leading to elevated cytokeratin 16 production. As expected, the expression of cytokeratin 16 was detected primarily in the suprabasal layer. The same pattern was observed in psoriatic lesional skin, i.e., mu-opiate receptor expression was significantly downregulated and cytokeratin 16 expression upregulated. These results suggest that the mu-opiate receptor system and its ligand beta-endorphin are involved in the pathogenesis of psoriasis, especially in terms of differentiation.

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