Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 25, 2019
- Source ID
- 10.7554/elife.48118
Entities
People
- Aakanksha Jain
- Bruce P. Bean
- Clifford J. Woolf
- Han-xiong Bear Zhang
- Jinbo Lee
- Laurel M. Heckman
- Masakazu Kotoda
- Maud Pascal
- Michelino Puopolo
- Nick A Andrews
- Pin W Liu
- Sebastien Talbot
- Seungkyu Lee
- Sooyeon Jo
- Thomas Jacquemont
Organizations
- Boston Children's Hospital
- Defense Advanced Research Projects Agency
- Harvard Medical School
- National Institute of Neurological Disorders and Stroke
- Stony Brook University School of Medicine
- Université de Montréal