ABSTRACT: When delivered to the oral mucosa, a variety of naturally occurring chemicals such as capsaicin from red chili peppers, piperine from black pepper, and nicotine from tobacco, cause a diffuse burning sensation often referred to as irritation. The burning sensation evoked by capsaicin increases when delivered repeatedly at 1 min intervals (sensitization), but then decreases markedly following a 10 min rest period (self‐desensitization. It is also interesting that following desensitization by capsaicin, irritant sensations evoked by other chemicals are also reduced (cross‐desensitization), suggesting that oral irritation from some agents may be mediated by a population of capsaicin‐sensitive trigeminal polymodal nociceptors.Although nicotine is a major component in tobacco smoke, little is known about its sensory properties. Accordingly, a study of the oral irritant effects of nicotine as compared with capsaicin was initiated.Whereas capsaicin (0.5 or 3 ppm; repeated at 1 min intervals over 10 min) evoked significantly stronger sensations (sensitization), there was a significant decrement in sensations to repeated application of nicotine (0.1%). After the subjects had received either repeated capsaicin or nicotine on one side of the tongue, a rest period ensued followed by a bilateral application of either capsaicin or nicotine. Subjects were, then, asked to choose which side yielded a stronger sensation (two‐alternative forced choice). Following capsaicin pretreatment, all subjects reported that capsaicin evoked a stronger sensation on the previously unseated side (capsaicin self‐desensitization). Similar self‐desensitization was observed with nicotine. Furthermore, nicotine was reported to evoke a significantly weaker sensation on the side of the tongue pretreated with capsaicin (cross‐desensitization). In contrast, equal numbers of subjects reported capsaicin to evoke a stronger sensation on either the nicotine‐pretreated side or the untreated side, indicating an absence of cross‐desensitization. These results are discussed in terms of physiological mechanisms that might underlie the contrasting sensory effects of nicotine versus capsaicin.