No release of histamine and substance P in capsaicin‐induced neurogenic inflammation in intact human skin in vivo: a microdialysis study

Abstract

Studies in rodents' skin have indicated substance P to be the main inflammatory mediator involved in neurogenic inflammation, acting partly by release of histamine from skin mast cells. The mediators released in neurogenic inflammation in human skin remain to be determined. To determine the effects of intradermally injected and topically applied capsaicin on the release of histamine and substance P and skin responses in intact human skin in vivo. Extracellular skin levels of histamine and substance P were measured by microdialysis technique and assayed by enzyme and radio immunoassays. Two kinds of dialysis fibres (210 microm, 2 kDa, and 500 microm, 20 kDa) were inserted intradermally into forearm skin for studies of histamine release to topically administered capsaicin and intradermally injected capsaicin and substance P. Baseline histamine skin levels were 8.0 +/- 0.7 nM. Intradermally injected capsaicin (0.3-30 microM, 7.5-750 pmol) caused significantly and dose-related flare and pain reactions, but no significant histamine release or weals. Intradermally injected substance P (1 and 3 microM, 25 and 75 pmol) released significant amounts of histamine (peak levels being 90 and 475 nM), evoked weal-and-flare reactions, but did not cause pain. Capsaicin 2% ointment, applied on the skin for 2.5 h, increased skin blood flow by 300-400% as measured by laser Doppler flowmetry, elicited a longstanding burning sensation, but did not release histamine. Substance P-like immunoreactivity (SP-LI) was below the 1.8 pM detection limit following insertion of 20 kDa dialysis fibre and after intradermal injection of capsaicin 3 microM. Intradermal injection of injection of 1 microM of substance P increased SP-LI levels to values greater than 4500 pM, confirming the ability of the dialysis fibre to recover this peptide. Capsaicin-induced neurogenic activation does not involve the release of histamine from mast cells or detectable amounts of substance P release from sensory nerves in normal human skin in vivo.