Taurolidine and congeners activate hTRPA 1 but not hTRPV 1 channels and stimulate CGRP release from mouse tracheal sensory nerves

Abstract Taurolidine has long been in clinical use as an antimicrobial irrigation that does not impede wound healing. It can even be administered intravenously (30 g/day) to treat sepsis or to exert newly recognized antineoplastic actions. Only one irritant effect is reported, that is, to temporarily induce burning pain of unknown origin when applied to body cavities or peripheral veins. The structure of the molecule suggested the chemoreceptor channel TRPA 1 as a potential target, which was verified measuring stimulated CGRP release from sensory nerves of the isolated mouse trachea and calcium influx in hTRPA 1‐transfected HEK 293 cells. With both methods, the concentration–response relationship of taurolidine exceeded the threshold value below 500  μ mol/L and 100  μ mol/L, respectively, and reached saturation at 1 mmol/L. The clinical 2% taurolidine solution did not evoke greater or longer lasting responses. The reversible tracheal response was abolished in TRPA 1 −/− but retained in TRPV 1 −/− mice. Consistently, hTRPV 1‐ HEK showed no calcium influx as a response, likewise native HEK 293 cells and hTRPA 1‐ HEK deprived of extracellular calcium did not respond to taurolidine 1 mmol/L. The metabolite taurultam and its oxathiazine derivative, expected to cause less burning pain, showed weak tracheal irritancy only at 10 mmol/L, acting also through hTRPA 1 but not hTRPV 1. In conclusion, taurolidine, its metabolite, and a novel derivative showed no unspecific cellular effects but selectively, concentration‐dependently and reversibly activated the irritant receptor TRPA 1 in CGRP ‐expressing, thus nociceptive, neurons. The clinical solution of 2% taurolidine (~70 mmol/L) can, thus, rightly be expected to cause transient burning pain and neurogenic inflammation.