hydroxy-alpha-sanshool (sanshool alkylamides)

Hydroxy-alpha-sanshool is one of the alkylamides contained in the fruit of the genus Zanthoxylum (Zanthoxylum), a component that produces a distinctive tingling or numbing sensation in the mouth. This is not a 「味」 (in translation: "taste") like sweetness, sourness, or bitterness, but rather a chemical stimulus sensation felt in the mouth, close to pain or temperature sensation. Most psychophysical experiments in human subjects are conducted not with sanshool itself from nature, but with the more stable derivative IBA.

This sensation is not merely a type of pain, but is intertwined with tactile sensation. When IBA is applied to the anterior third of the tongue, the R-index indicating tactile discrimination clarity decreased from 93.8 to 84.3 with one force of von Frey filament and from 86.9 to 75.2 with another filament, and tactile sensation became duller. Capsaicin, used as a control, did not have the same effect. Conversely, there is also an experiment showing that when sustained pressure is applied to the lip, the tingling sensation from sanshool itself is suppressed to approximately 24.7% of baseline; thus, tingling and tactile sensation have a mutually influential relationship.

Which receptor mediates this tingling sensation remains disputed among studies. In one mouse experiment, sanshool excited 52.3% of sensory neurons, with strong effects on the two-pore potassium channels KCNK3 and KCNK18 (IC50 of 30.3 and 50.2 uM respectively), and the response was unchanged in mice lacking both TRPV1 and TRPA1. However, in another study, hydroxy-alpha-sanshool has been reported to activate TRPV1 as an agonist at EC50 1.1 uM and TRPA1 at EC50 69 uM, and in mice lacking TRPV1, avoidance behavior to 1 mM sanshool is treated as nearly abolished. In human experiments, even when pain-sensing channels are adapted with capsaicin or mustard oil, the tingling from sanshool is not weakened, and the numbness on the lip is positioned in a tactile-like neural pathway (RA1). One of the authors pointed out that this discrepancy may be due to differences in test temperature, and the mechanism remains unsettled.

Sanshool as a pungent component of sansho is also a long-studied research subject. The original 1931 paper records that ether extract was obtained from the fruit of Japanese sansho (Xanthoxylum piperitum D.C.), and crude sanshool was isolated by reduction, fractional distillation, and decomposition, the methods of that time. This is not a study identified and quantified as a single compound by modern analysis, but is positioned as a historical first step.