RAGE mediates LPS-induced inflammatory pain in human skin

Inflammatory pain is a major clinical challenge, yet appropriate human models mimicking local infection are lacking. We established a novel human pain model based on intradermal administration of lipopolysaccharide (LPS), a component of Gram-negative bacteria, and investigated the time course and underlying molecular mechanisms of inflammatory pain hypersensitivity. In a placebo-controlled pilot study with 12 healthy subjects, the intradermal LPS injection induced hyperaemia peaking at 4.5 h and mechanical hypersensitivity peaking at 6 h. Hypersensitivity to increasingly acidic injections and mechanical pinch lasted longer than hyperaemia. The double-blind, randomized, placebo-controlled full crossover main study was completed by 40 subjects and investigated the role of the Receptor for Advanced Glycation End-products (RAGE). Co-injection of the RAGE antagonist azeliragon largely reduced LPS-induced hyperaemia (-87%) and significantly attenuated hypersensitivity to mechanical (-55%) and increasingly acidic stimuli (-40%). In contrast, the Toll-like receptor 4 antagonist resatorvid had no effect on any readout. In both naive and inflamed skin, TRPV1 antagonist BCTC inhibited the majority of acid-induced pain. LPS-induced inflammation caused a substantial shift in the pH sensitivity of pain, suggesting that even mild tissue acidification contributes to inflammatory pain. The human LPS skin inflammation model is largely RAGE-dependent, highlighting its potential as a target in inflammation.