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Extracts from the toothache tree (Zanthoxylum) are used to treat inflammatory pain, such as toothache and arthritis.Hydroxy-α-sanshool (sanshool) is a major alkylamide in extracts from Zanthoxylum plants.Sanshool treatment in mice caused a selective attenuation of mechanical sensitivity under naïve and inflammatory conditionsSanshool inhibits Aδ mechanonociceptors that mediate both sharp acute pain and inflammatory pain, and inhibits the activity of multiple voltage-gated sodium channel subtypes, among which Nav1.7 is the most strongly affected.Our data implicate Nav1.7 as a key mediator of inflammatory mechanical pain in ‘fast pain’ mechanosensory neurons.In traditional medicine, the ‘toothache tree’ and other plants of the Zanthoxylum genus have been used to treat inflammatory pain conditions, such as toothache and rheumatoid arthritis. Here we examined the cellular and molecular mechanisms underlying the analgesic properties of hydroxy-α-sanshool, the active alkylamide produced by Zanthoxylum plants. Consistent with its analgesic effects in humans, sanshool treatment in mice caused a selective attenuation of mechanical sensitivity under naïve and inflammatory conditions, with no effect on thermal sensitivity. To elucidate the molecular mechanisms by which sanshool attenuates mechanical pain, we performed single fibre recordings, calcium imaging and whole-cell electrophysiology of cultured sensory neurons. We found that: (1) sanshool potently inhibits Aδ mechanonociceptors that mediate both sharp acute pain and inflammatory pain; (2) sanshool inhibits action potential firing by blocking voltage-gated sodium currents in a subset of somatosensory neurons, which express a unique combination of voltage-gated sodium channels; and (3) heterologously expressed Nav1.7 is most strongly inhibited by sanshool as compared to other sodium channels expressed in sensory neurons. These results suggest that sanshool targets voltage-gated sodium channels on Aδ mechanosensory nociceptors to dampen excitability and thus induce ‘fast pain’ analgesia.