Spider venom-derived peptide induces hyperalgesia in Nav1.7 knockout mice by activating Nav1.9 channels

Abstract

The sodium channels Na_v1.7, Na_v1.8 and Na_v1.9 are critical for pain perception in peripheral nociceptors. Loss of function of Na_v1.7 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_v4.2, restores nociception in Na_v1.7 knockout (Na_v1.7-KO) mice by enhancing the excitability of dorsal root ganglion neurons. HpTx1 inhibits Na_v1.7 and activates Na_v1.9 but does not affect Na_v1.8. This toxin produces pain in wild-type (WT) and Na_v1.7-KO mice, and attenuates nociception in Na_v1.9-KO mice, but has no effect in Na_v1.8-KO mice. These data indicate that HpTx1-induced hypersensitivity is mediated by Na_v1.9 activation and offers pharmacological insight into the relationship of the three Na_v channels in pain signalling.