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Lappaconitine (LA) has been widely used for postoperative and cancer pain control.LA exhibits excellent analgesic activity with a longer effective time than common local anesthetics such as tetracaine and bupivacaine.However,the mechanisms underlying the featured analgesic activity of LA remain largely unknown.Here,we report that LA is an inhibitor of voltage-gated sodium channel 1.7 (Nav1.7) stably expressed in human embryonic kidney (HEK293) cells.LA inhibited Nav1.7 in a voltage-dependent manner with an IC50 value (with 95％ confidence limits) of 27.67 (15.68-39.66) μmol/L when the cell was clamped at-70 mV.In comparison with the quick and reversible inhibition of Nay1.7 by tetracaine and bupivacaine,the inhibitory effect of LA was rather slow and irreversible.It took more than 10 min to achieve steady-state inhibition when LA (300 μmol/L) was administered.Unlike tetracaine and bupivacaine,LA affected neither the voltage-dependent activation nor the inactivation of the channels.Five residues in domain ill and domain Ⅳ have been reported to be critical for the effects of the two local anesthetics on Nav channels.But our mutant study revealed that only two residues (F1737,N1742) located in domain Ⅳ were necessary for the inhibitory activity of LA.The slow onset,irreversibility,and lack of influence on channel activation and inactivation accompanied with the different molecular determinants suggest that LA may inhibit Nav1.7 channels in a manner different from local anesthetics.These results may help to understand the featured analgesic activity of LA,thus benefiting its application in the clinic and future drug development.