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

Xi Zhou,Li Wang,Lulu Li,Jing Yu Liu,Shuijiao Peng,Qingfeng Zhang,Minzhi Chen,Xianwei Zhang,Zhonghua Liu,Yazhou Huang,Songping Liang,Tingbin Ma,Zhouquan Wang,Luyao Yang,Zhen Xiao

doi:10.1038/s41467-020-16210-y

Abstract

The sodium channels Nav1.7, Nav1.8 and Nav1.9 are critical for pain perception in peripheral nociceptors. Loss of function of Nav1.7 leads to congenital insensitivity to pain in humans. Here we show that the spider peptide toxin called HpTx1, first identified as an inhibitor of Kv4.2, restores nociception in Nav1.7 knockout (Nav1.7-KO) mice by enhancing the excitability of dorsal root ganglion neurons. HpTx1 inhibits Nav1.7 and activates Nav1.9 but does not affect Nav1.8. This toxin produces pain in wild-type (WT) and Nav1.7-KO mice, and attenuates nociception in Nav1.9-KO mice, but has no effect in Nav1.8-KO mice. These data indicate that HpTx1-induced hypersensitivity is mediated by Nav1.9 activation and offers pharmacological insight into the relationship of the three Nav channels in pain signalling.

Highlights

The sodium channels Nav1.7, Nav1.8 and Nav1.9 are critical for pain perception in peripheral nociceptors
A total of 65.5% of neurons (19 out of 29) showed a decrease in rheobase in the presence of HpTx1 (Supplementary Table 2), and these neurons that exhibited a reduction in rheobase showed enhanced action potentials (APs) firing in response to depolarizing currents (Fig. 2f, g). These results indicated that HpTx1 might enhance the membrane excitability of some small dorsal root ganglion (DRG) neurons from WT, fNav1.7, and Nav1.7-KO mice by depolarizing resting membrane potential (RMP), decreasing current threshold, and increasing AP firing
We further found that HpTx1 had no evident effect on voltage-gated potassium channels in DRG neurons, and the current–voltage curves were not altered by HpTx1 treatment

Summary

Introduction

The sodium channels Nav1.7, Nav1.8 and Nav1.9 are critical for pain perception in peripheral nociceptors. Homozygous or compound heterozygous loss-of-function mutations in Nav1.7 lead to congenital insensitivity to pain (CIP)[2,5,6], whereas gain-of-function mutations cause episodic pain (i.e., primary erythromelalgia and paroxysmal extreme pain disorder) in humans[7,8,9]. This evidence indicates that selectively blocking Nav1.7 may be useful to relieve pain. We provide pharmacological evidence that cross talk among Nav1.7, Nav1.8, and Nav1.9 may affect AP firing and pain signaling, thereby establishing an important role for Nav1.9 in pain perception

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Results

Conclusion