(Vienna, 07-09-2026) Inflammation often makes tissue particularly sensitive to pain – for example, in the case of infections, injuries or chronic diseases. Until now, it has been difficult to investigate exactly how this hypersensitivity arises in humans under controlled conditions. Researchers at MedUni Vienna have now developed a skin model that allows them to trigger a localised, infection-like inflammation and specifically investigate its effect on pain perception. Their findings revealed that a different receptor than previously assumed plays a central role. The results, which have recently been published in the journal "Nature Communications", could therefore provide a new starting point for the development of therapies against inflammatory pain.
For the new model, the research team used lipopolysaccharide (LPS), a component of the outer membrane of certain bacteria. Very small amounts of LPS were injected into the skin of healthy study participants. In a pilot study involving twelve people, this triggered a localised inflammatory reaction lasting several hours without causing an actual infection, as no living bacteria are administered. The research team then investigated the underlying mechanisms in a double-blind, randomised and placebo-controlled study involving 40 healthy participants. "Using this model, we were able, for the first time, to investigate in a highly targeted manner how local inflammation develops in humans and how sensitivity to different pain stimuli changes in the process," says Felix Resch, lead author of the study at the Institute of Physiology at MedUni Vienna.
Inflammatory response works differently than previously thought
It was already known from cell and animal models that the bacterial component LPS exerts its pro-inflammatory effect primarily via the so-called TLR4 receptor. However, it was unclear whether this also applied to humans. In the current study, blocking this receptor had no significant effect on inflammation or pain sensitivity. The situation was markedly different, however, with the RAGE receptor. RAGE is a receptor found on skin, immune and nerve cells that transmits inflammatory signals and can therefore also influence pain sensitivity. When RAGE was specifically blocked with azeliragon, the increased skin blood flow – a sign of inflammation – decreased by 87 per cent. The increased sensitivity to pressure and to a slightly acidic environment – such as that which can develop in inflamed tissue – was also significantly reduced. "What was particularly surprising was that blocking TLR4 had virtually no effect, whilst inhibiting RAGE greatly attenuated the inflammatory response. This shows that the mechanisms in humans may differ from previous assumptions based on cell and animal models," explains Stefan Heber from the Institute of Physiology at MedUni Vienna.
RAGE comes into focus as a therapeutic target
The results make RAGE a potential target for the further development of therapies against inflammation and pain, particularly those caused by bacteria. Whether targeted inhibition of the receptor can be utilised therapeutically must be investigated in further studies. "The new model enables us to investigate the mechanisms of inflammatory pain directly in humans and to specifically test potential pharmacological targets. Based on these findings, RAGE is a particularly interesting candidate for further research," says Michael Fischer, Head of the Institute of Physiology at MedUni Vienna.
Publication: Nature Communications
RAGE mediates LPS-induced inflammatory pain in human skin – a double-blind, randomized, placebo-controlled full crossover study
Felix J. Resch, Sibylle Pramhas, Bernd Jilma, Sabine Sator, Stefan Heber, Michael J.M. Fischer
DOI: 10.1038/s41467-026-76771-2
https://www.nature.com/articles/s41467-026-76771-2
Die Studie wurde durch den Österreichischen Wissenschaftsfonds FWF im Rahmen des Grants KLI-924 unterstützt.