The capsaicin receptor TRPV1, co-expressed with CGRP in nociceptive nerve fibers of the airways, acts as a most polymodal irritant receptor being activated by acids, heat, particulate matter, many exogenous and endogenous chemicals. Noxious heat (45°, 52°C) caused significant and graded increases of iCGRP release (over baseline) with a Q10 of 3, and it was the same in TRPV1-/-and +/+. The heat response was 5-fold enhanced by (pre-) treatment with the TRPV1 agonist ethanol, 4-fold enhanced with the TRPV1-2-3 agonist 2-APB (inactive at 37°C), and significantly increased by the putative TRPV3 agonist camphor, but these sensitising effects were all lost in TRPV1-/-. Proton stimulation resulted in a bell-shaped concentration-response with a maximum at pH 5.7 and a threshold at pH 6.7; the responses were greatly reduced but not abolished in TRPV1-/-. Co-application of amiloride, that blocks ASIC channels, was effective but only in wildtype mice. In conclusion, TRPV1 plays an important role in tracheal acid sensing and in chemically induced sensitization to heat but not in basic neuronal heat sensitivity, which also does not seem to employ TRPV2/3. Acknowledgment to John B.Davis for the TRPV1 transgenic mouse strain.