Psychophysical Evaluation of a Sanshool Derivative (Alkylamide) and the Elucidation of Mechanisms Subserving Tingle

Previous studies investigated the neural and molecular underpinnings of the tingle sensation evoked by sanshool and other natural or synthetic alkylamides. Currently, we sought to characterize the psychophysical properties associated with administration of these compounds. Like other chemesthetic stimuli, the synthetic tingle analog isobutylalkylamide (IBA) evoked a sensation that was temporally dynamic. Repeated IBA application at short (30 sec) interstimulus intervals (ISI) resulted in a tingle sensation that increased across trials. Application at longer ISIs (∼30 min) resulted in a sensation of decreased intensity consistent with self-desensitization. Prior treatment with the TRPV1 or TRPA1 agonists, capsaicin and mustard oil did not cross-desensitize the tingle sensation evoked by IBA suggesting that neither TRPV1 nor TRPA1 participate in the transduction mechanism sub-serving tingle. When evaluated over 30-min time period, lingual IBA evoked a sensation that was described initially as tingling and pungent but after approximately 15 min, as a cooling sensation. Further, we found that the sensation evoked by lingual IBA was potentiated by simultaneous application of cold (0°C) and cool (21°C) thermal stimuli but was unaffected by warm (33°C) and hot (41°C) temperatures. Finally, to test the hypothesis that the tingling sensation is subserved by the activation of mechanosensitve fibers, we evaluated lingual tactile thresholds in the presence and absence of lingual IBA. The presence of IBA significantly raised lingual tactile thresholds, whereas capsaicin did not, identifying a role for mechanosensitive fibers in conveying the tingle sensation evoked by sanshool-like compounds. Collectively, these results show that lingual alkylamide evokes a complex sensation that is temporally dynamic and consistent with in vitro and in vivo experiments suggesting these compounds activate mechanosensitve neurons via blockade of KCNK two-pore potassium channels to induce the novel tingling sensation.