Abstract
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.
Highlights
Alkylamides are a unique class of compounds that elicit a distinctive tingling sensation when applied to mucosal surfaces [1]
Electrophysiological studies have shown that a-hydroxy-sanshool activates low and high threshold cold-sensitive fibers as well as low threshold mechanosensitive fibers of the rat lingual nerve [1]. Consistent with these findings, we recently reported that when injected into the rat hindpaw, a stable derivative of a-hydroxysanshool activated both widedynamic range (WDR) and low-threshold mechanoreceptors (LTM) in the spinal dorsal horn [8]
Whereas most irritants can be cross-desensitized by prior application of TRPV1 or TRPA1 agonists, IBA was not
Summary
Alkylamides are a unique class of compounds that elicit a distinctive tingling sensation when applied to mucosal surfaces [1]. A-hydroxy-sanshool and spilanthol are found in Szechuan pepper (Xanthoxylum piperitum) and Jambu fruit (Acmella oleracea), respectively and are used in ethnic cuisines to provide unique oral sensations during the consumption of meals [2,3]. Medicinal uses of these compounds have been described; the plants have been used indigenously as analgesics, digestive aids and are purported to stimulate immune responses [4]. Electrophysiological studies have shown that a-hydroxy-sanshool activates low and high threshold cold-sensitive fibers as well as low threshold mechanosensitive fibers of the rat lingual nerve [1]. Subsequent reports suggest that activation of both nociceptive and mechanosensitve cells occurs through the unique ability of alkylamides to inhibit background potassium conductances through anestheticsensitive two-pore potassium channels (KCNK3, KCNK9 and KCNK18; [11])
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