Nociceptor activation and protein extravasation induced by inflammatory mediators in human skin

Protein extravasation (PE) is known to play an important role in inflammatory conditions. In this study we used dermal microdialysis to apply inflammatory mediators (histamine, bradykinin, serotonin) to human skin. Locally induced PE was compared to pain ratings and axon reflex erythema measured simultaneously. Linear microdialysis capillaries (outer diameter 0.4 mm; cut-off 3000 kDa) were inserted intracutaneously at a length of 1.5 cm in the volar forearm of healthy volunteers. The capillaries were perfused with Ringer's solution at a constant flow rate of 4 microl/min. The perfusate was sampled at 15-min intervals and was analysed for total protein concentration. After a baseline of 60 min, the perfusion was switched to inflammatory mediators for 30 min and then back to vehicle again. Sensations evoked by the stimulation were assessed on a visual analogue scale and visible axon reflex erythema was measured planimetrically.Dose-dependent increases in PE could be assessed for all inflammatory mediators tested. Bradykinin (10(-7)M) induced a significant PE, whereas serotonin was effective only at a concentration of 10(-3)M. While serotonin in lower concentrations induced moderate burning pain and an axon reflex flare but no PE, bradykinin provoked PE without pain or axon reflex flare at a concentration of 10(-7)M. Application of histamine similarly evoked PE at lower concentrations as compared to the induction of itch sensation and axon reflex flare. It is concluded that there is no link between nociceptor activation and protein extravasation induced by inflammatory mediators in healthy human skin.