Exogenous but not endogenous substance P releases histamine from isolated human skin fragments

Neuropeptides such as substance P are released from nerve terminals following the stimulation of sensory fibers, and are thought to participate in neurogenic inflammation in the skin; it is often speculated that mast cell activation is an intermediate step in this process. In the present study we addressed this hypothesis using freshly obtained skin explants derived from human neonatal foreskins or adult skin resections. The results demonstrate that when substance P is released from human skin by incubation in the presence of capsaicin (10^-5 M), no histamine is released from human isolated skin fragments. In each experiment human recombinant stem cell factor and/or exogenously applied substance P effectively evoked histamine release from the explants, attesting to the viability of the mast cells in the preparation. The concentrations of exogenously applied substance P required to elicit histamine release, however, were large (> 10 μM). These results indicate that substance P released from cutaneous sensory nerve fibers does not reach sufficient concentrations in the skin to degranulate mast cells. These data support the hypothesis that the vascular effects of neurogenic inflammation occur independently of mast cell activation.