Spider venom-derived peptide induces hyperalgesia in Na(v)1.7 knockout mice by activating Na(v)1.9 channels

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.