Abstract

The voltage-gated sodium channel Nav1.8 is preferentially expressed in peripheral nociceptive neurons and contributes to inflammatory and neuropathic pain. Therefore, Nav1.8 has emerged as one of the most promising analgesic targets for pain relief. Using large-scale screening of various animal-derived toxins and venoms for Nav1.8 inhibitors, here we identified μ-EPTX-Na1a, a 62-residue three-finger peptide from the venom of the Chinese cobra (Naja atra), as a potent inhibitor of Nav1.8, exhibiting high selectivity over other voltage-gated sodium channel subtypes. Using whole-cell voltage-clamp recordings, we observed that purified μ-EPTX-Na1a blocked the Nav1.8 current. This blockade was associated with a depolarizing shift of activation and repolarizing shift of inactivation, a mechanism distinct from that of any other gating modifier toxin identified to date. In rodent models of inflammatory and neuropathic pain, μ-EPTX-Na1a alleviated nociceptive behaviors more potently than did morphine, indicating that μ-EPTX-Na1a has a potent analgesic effect. μ-EPTX-Na1a displayed no evident cytotoxicity and cardiotoxicity and produced no obvious adverse responses in mice even at a dose 30-fold higher than that producing a significant analgesic effect. Our study establishes μ-EPTX-Na1a as a promising lead for the development of Nav1.8-targeting analgesics to manage pain.

Highlights

  • The voltage-gated sodium channel Nav1.8 is preferentially expressed in peripheral nociceptive neurons and contributes to inflammatory and neuropathic pain

  • This peptide belongs to the family of three-finger peptide toxins and shares high sequence identity with cardiotoxin A5, cardiotoxin-like basic polypeptides (CLBPs), and some other cardiotoxins (CTXs) [20, 21]

  • Nav1.8 was proven to be a crucial target for pain management, and identification of Nav1.8-selective inhibitors is urgently needed

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Summary

Introduction

The voltage-gated sodium channel Nav1.8 is preferentially expressed in peripheral nociceptive neurons and contributes to inflammatory and neuropathic pain. Using whole-cell voltage-clamp recordings, we observed that purified ␮-EPTX-Na1a blocked the Nav1.8 current This blockade was associated with a depolarizing shift of activation and repolarizing shift of inactivation, a mechanism distinct from that of any other gating modifier toxin identified to date. Abnormal glucose metabolism leads to the accumulation of high concentrations of the metabolite methylglyoxal, which modifies Nav1.8 and facilitates nociceptive neuron firing, leading to diabetes-related metabolic hyperalgesia [9] These significant findings have established the Nav1.8 as a crucial target for the treatment of various excruciating pain

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