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Notes: Stress is said to induce itchiness of the skin and exacerbate inflammatory skin diseases such as atopic dermatitis. In this context, stress mediators such as the neuropeptide substance P play a role as immunmodulators and in a wider sense growth factors. For example, we were recently able to show that stress or treatment of mice with substance P is associated with mast cell degranulation, increased cutaneous inflammation and increased apoptosis in the hair follicle. However, local interactions between the nervous and immune systems, especially under perceived stress, have rarely been reported. Here, we show for the first time, that 24 and 48 h after sonic stress exposure, the number of SP-immunoreactive nerve fibres in the back skin of C57BL/6 mice with all there hair follicles in the resting phase of the hair cycle (telogen, low numbers of cutaneous nerve fibres) increased significantly over non-stressed mice with the strongest increase after 24 h. Such substance P immunoreactive nerve fibres contacted mast cells more frequently, which became significant after 48 h. At the same time, the percentage of degranulated mast cells increased significantly after 24 and 48 h with the strongest increase after 48 h when apoptotic cells also became significantly upregulated. The same stressor increased dermal infiltration, e.g. by eosinophils in C57BL/6 mice with experimentally induced allergic dermatitis over mice that were either stressed or had allergic dermatitis as well as over untreated controls. Increased infiltration was associated with increased epidermal thickness in stressed mice with allergic dermatitis and with an increased number of VCAM-immunoreactive blood vessels. At the same time, the percentage of degranulated mast cells increased significantly, and the number of substance P-immunoreactive peptidergic sensory nerve fibres decreased in the acute allergic dermatitis lesions. By semiquantitative RT-PCR, allergic dermatitis increased cutaneous IL-4 and to a lesser degree IFN-γ production, but this was not affected by stress. Ultrastructural investigation showed unmyelinated peptidergic nerve fibres in a state of deterioration close to degranulating mast cells and eosinophils in the skin of stressed mice with allergic dermatitis, suggesting a decreased number of substance P-immunoreactive nerve fibres due to active release of SP. This may lead to an upregulation of endothelial adhesion molecules and increased infiltration by immunocytes to the skin but at mRNA level does not alter the production of classical atopy-related cytokines in skin. These data provide first evidence for stress-induced exacerbation of cutaneous allergic diseases such as atopic dermatitis by local interaction of the peripheral nervous system with substance P.