RAGE mediates LPS-induced inflammatory pain in human skin - a double-blind, randomised, placebo-controlled full crossover study.

Inflammatory pain is a major clinical challenge, yet appropriate human models mimicking local infection are lacking. We established a human pain model based on intradermal administration of lipopolysaccharide, a component of Gram-negative bacteria, and investigated the time course and underlying molecular mechanisms of inflammatory pain hypersensitivity. A placebo-controlled pilot study with 12 healthy subjects showed that intradermal lipopolysaccharide injection induces hyperaemia peaking at 4.5 h and mechanical hypersensitivity peaking at 6 h. Hypersensitivity to increasingly acidic injections and mechanical pinch lasts longer than hyperaemia. The double-blind, randomised, placebo-controlled full crossover main study (NCT07092215) included 40 healthy subjects and investigated the role of the Receptor for Advanced Glycation End-products. The primary hypothesis was: 'The blood flow is different in lipopolysaccharide-injected skin spots compared to lipopolysaccharide-injected skin spots where azeliragon is co-injected'. The two secondary hypotheses were: 'Acid-induced pain is different in lipopolysaccharide-injected skin spots compared to lipopolysaccharide-injected skin spots where azeliragon is co-injected' and 'Mechanical pinch-induced pain is different in lipopolysaccharide-injected skin spots compared to lipopolysaccharide-injected skin spots where azeliragon is co-injected'. Co-injection of the respective antagonist azeliragon largely reduces lipopolysaccharide-induced hyperaemia (-87%) and significantly attenuates hypersensitivity to mechanical (-55%) and increasingly acidic stimuli (-40%). In contrast, the Toll-like receptor 4 antagonist resatorvid has no effect on these readouts. In both naïve and inflamed skin, the TRPV1 antagonist BCTC inhibits the majority of acid-induced pain. Lipopolysaccharide-induced inflammation causes a substantial shift in the pH sensitivity of pain, suggesting that even mild tissue acidification contributes to inflammatory pain. The human lipopolysaccharide skin inflammation model depends largely on the Receptor for Advanced Glycation End-products, highlighting its potential as a target in inflammation.