High concentrations of nicotine, as in the saliva of oral tobacco consumers or in smoking cessation aids, have been shown to sensitize/activate recombinant rTRPV1 and mTRPA1 channels. Measuring stimulated CGRP release from the isolated mouse trachea we established a bimodal concentration-response relationship with a threshold below 10µM (-)-nicotine, a maximum at 100µM, an apparent nadir between 0.5 and 10mM and a renewed increase at 20mM. The first peak was unchanged in TRPV1/A1 double-null mutants as compared to wildtypes and was abolished by specific nicotinic acetylcholine receptor (nAChR) inhibitors and by camphor, discovered to act as nicotinic antagonist. The nicotine response at 20mM was strongly pHe dependent, five-times greater at pH9 than 7.4, indicating that intracellular permeation of the (uncharged) alkaloid was required to reach the TRPV1/A1 binding sites. The response was strongly reduced in both null mutants, more so in double-null mutants. Measuring calcium transients in nodose/jugular and dorsal root ganglion neurons in response to nicotine 100µM, 48% of the vagal but only 14% of the somatic sensory neurons were activated, the latter very weakly. However, nicotine 20mM at pH9 repeatedly activated almost every single cultured neuron, partly by releasing intracellular calcium and independent of TRPV1/A1 and nAChRs. In conclusion, in mouse tracheal sensory nerves nAChRs are 200-fold more sensitive to nicotine than TRPV1/A1; they are widely co-expressed with the capsaicin receptor among vagal sensory neurons and twice as abundant as TRPA1. Nicotine is the major stimulant in tobacco, and its sensory impact through nAChRs should not be disregarded.