Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation

Elife. 2019 Nov 25;8:e48118. doi: 10.7554/eLife.48118.


Voltage-dependent sodium and calcium channels in pain-initiating nociceptor neurons are attractive targets for new analgesics. We made a permanently charged cationic derivative of an N-type calcium channel-inhibitor. Unlike cationic derivatives of local anesthetic sodium channel blockers like QX-314, this cationic compound inhibited N-type calcium channels more effectively with extracellular than intracellular application. Surprisingly, the compound is also a highly effective sodium channel inhibitor when applied extracellularly, producing more potent inhibition than lidocaine or bupivacaine. The charged inhibitor produced potent and long-lasting analgesia in mouse models of incisional wound and inflammatory pain, inhibited release of the neuropeptide calcitonin gene-related peptide (CGRP) from dorsal root ganglion neurons, and reduced inflammation in a mouse model of allergic asthma, which has a strong neurogenic component. The results show that some cationic molecules applied extracellularly can powerfully inhibit both sodium channels and calcium channels, thereby blocking both nociceptor excitability and pro-inflammatory peptide release.

Keywords: Cav2.2; Nav1.7; asthma; calcitonin gene-related peptide; dorsal root ganglion; inflammatory peptide; mouse; neuroscience.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bupivacaine / pharmacology
  • Calcium / metabolism
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, N-Type / genetics*
  • Calcium Signaling / drug effects
  • Disease Models, Animal
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / pathology
  • Humans
  • Lidocaine / analogs & derivatives
  • Lidocaine / pharmacology
  • Mice
  • Neurogenic Inflammation / drug therapy*
  • Neurogenic Inflammation / genetics
  • Neurogenic Inflammation / pathology
  • Nociceptors
  • Pain / drug therapy*
  • Pain / genetics
  • Pain / pathology
  • Sodium Channel Blockers / pharmacology
  • Sodium Channels / genetics*


  • Calcium Channel Blockers
  • Calcium Channels, N-Type
  • Sodium Channel Blockers
  • Sodium Channels
  • QX-314
  • Lidocaine
  • Calcium
  • Bupivacaine