Histamine is released in the wheal but not the flare following challenge of human skin in vivo: a microdialysis study

Abstract

The mediator mechanisms of the cutaneous wheal and flare response, which underlies allergic skin and urticarial conditions, are controversial. The wheal results primarily from a direct effect of histamine on the local vascular bed but to what extent does histamine diffuse within the wheal? The flare is neurogenic, in origin, being disseminated within the dermis by axon reflexes, but do the neuropeptides released from the nerve endings cause the vasodilatation directly or do they induce the further release of histamine which then transduces the flare? We have addressed these questions by inserting 216 microns diameter microdialysis fibres into the dermis within the different areas of the wheal and flare to monitor changes in histamine levels provoked by intradermal injections of histamine, allergen, codeine and substance P. Twenty-one subjects participated in the investigations. The histamine concentration in unprovoked skin was 10.5 +/- 0.6 nM. As the dialysis efficacy was approximately 50%, this equates to tissue concentrations of 20 nM. All provicants released large amounts of histamine at the injection site, maximum histamine levels being 337-1293 nM. Diffusion of histamine within the wheal was poor, levels at 2.3 mm and 3.7 mm from the site of injection being 4-22% and 0.2-3.7% respectively of those 1 mm from the injection site. No increased histamine levels were detected in the flare with any provicant. Atraumatic delivery to the skin of histamine in infusion concentrations of 30-10,000 nM caused concentration-related effects, at least 100 nM being necessary to induce a significant increase in skin blood flow, a threshold of 300-1000 being required to stimulate a visible flare and a measurable erythema, and 3000-10,000 nM being the minimum for induction of a wheal. Thus the skin blood vessels and nerves are responsive to histamine, but at relatively high concentrations. These data support the theory that the flare reaction to focal histamine injection or release is a neurogenic reflex not involving histamine release at its effector end.