Spider venom-derived peptide induces hyperalgesia in Na1.7 knockout mice by activating Na1.9 channels.

The sodium channels Na1.7, Na1.8 and Na1.9 are critical for pain perception in peripheral nociceptors. Loss of function of Na1.7 leads to congenital insensitivity to pain in humans. Here we show that the spider peptide toxin called HpTx1, first identified as an inhibitor of K4.2, restores nociception in Na1.7 knockout (Na1.7-KO) mice by enhancing the excitability of dorsal root ganglion neurons. HpTx1 inhibits Na1.7 and activates Na1.9 but does not affect Na1.8. This toxin produces pain in wild-type (WT) and Na1.7-KO mice, and attenuates nociception in Na1.9-KO mice, but has no effect in Na1.8-KO mice. These data indicate that HpTx1-induced hypersensitivity is mediated by Na1.9 activation and offers pharmacological insight into the relationship of the three Na channels in pain signalling.