Abstract

The sodium channels Na v 1.7, Na v 1.8 and Na v 1.9 are critical for pain perception in peripheral nociceptors. Loss of function of Na v 1.7 leads to congenital insensitivity to pain in humans. Here we show that the spider peptide toxin called HpTx1, first identified as an inhibitor of K v 4.2, restores nociception in Na v 1.7 knockout (Na v 1.7-KO) mice by enhancing the excitability of dorsal root ganglion neurons. HpTx1 inhibits Na v 1.7 and activates Na v 1.9 but does not affect Na v 1.8. This toxin produces pain in wild-type (WT) and Na v 1.7-KO mice, and attenuates nociception in Na v 1.9-KO mice, but has no effect in Na v 1.8-KO mice. These data indicate that HpTx1-induced hypersensitivity is mediated by Na v 1.9 activation and offers pharmacological insight into the relationship of the three Na v channels in pain signalling.