Inhibitory effects of lappaconitine on the neuronal isoforms of voltage-gated sodium channels

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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 Nav1.7 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 III 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.

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We thank Dr. Norbert Klugbauer (Albert-Ludwigs-Universität Freiburg, Freiburg, Germany) for the gift of hNav1.7 cDNA. This work was supported by the Personalized Medicines “Molecular Signature-Based Drug Discovery and Development” (Strategic Priority Research Program of the Chinese Academy of Sciences, Grant No. XDA12040221 and XDA15050308), the National Natural Science Foundation of China (81603096, 81773707, 61327014, and 61433017), and the Shanghai Science and Technology Innovation Fund 15431901500.

Author contributions

Z-BG and YG designed and conceived the experiments; Y-FL and Y-MZ performed the experiments and contributed equally to the project; all authors analyzed the data; Y-FL, Y-MZ, and Z-BG wrote the paper.

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Correspondence to Yong Gan or Zhao-bing Gao.

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The authors declare no competing financial interests.

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  • voltage-gated sodium channel 1.7
  • analgesics
  • lappaconitine
  • tetracaine
  • bupivacaine

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