Inducible desensitization to capsaicin with repeated low-dose exposure in human volunteers

Responses to capsaicin are reduced following repeated exposure, a phenomenon known as capsaicin desensitization. Heavy consumers of chilies consistently report reduced oral burn relative to infrequent consumers, presumably due to chronic desensitization. However, the mechanism(s) underlying capsaicin desensitization remain poorly understood. We hypothesized that reduced response to capsaicin due to repeated oral exposure may result from a change in the expression of the capsaicin receptor (TRPV1) gene. To test this, we conducted two longitudinal desensitization studies in healthy human volunteers. In Study 1, 51 adults completed a 17-day capsaicin desensitization protocol. The study consisted of three in-person visits where they were asked to sample stimuli, including 3, 6, and 9 ppm capsaicin, and rate intensity on a general labeled magnitude scale (gLMS). Between days 3 & 17, participants rinsed at home with 6 ppm capsaicin (n = 31) or a control (n = 20) solution (20 uM sucrose octaccetate; SOA) twice a day. Before and after the oral exposure protocol, a clinician collected fungiform papillae. Participants randomized to the capsaicin rinse showed a statistically significant reduction in oral burn ratings that was not observed in controls, indicating repeated low-dose exposure can systematically induce desensitization. TRPV1 expression was not associated with reported capsaicin burn, and there was no evidence of a decrease in TRPV1 expression following capsaicin exposure. In Study 2, participants (n = 45) rinsed with 6 ppm capsaicin in a similar protocol, rating capsaicin, vanillyl butyl ether (VBE), cinnamaldehyde, ethanol, menthol, and sucrose on days 1, 3, & 17. Burn from capsaicin, VBE, cinnamaldehyde, and ethanol all showed a statistically significant change - capsaicin, VBE and cinnamaldehyde burn all dropped ∼20 %, and a larger reduction was seen for ethanol - while menthol cooling and sucrose sweetness did not change. Collectively, this suggests reductions in oral burn following chronic capsaicin exposure generalizes to other stimuli (i.e., cross desensitization) and this cannot be explained by a change in TRPV1 mRNA expression. More work is needed to elucidate the underlying mechanism for capsaicin desensitization in the oral cavity.