Seungkyu Lee1,†, Sooyeon Jo2,†, Se´ bastien Talbot3, Han-Xiong Bear Zhang2, Masakazu Kotoda1, Nick A Andrews1, Michelino Puopolo4, Pin W Liu2, Thomas Jacquemont1, Maud Pascal1, Laurel M Heckman1, Aakanksha Jain1, Jinbo Lee5, Clifford J Woolf1,2,*, Bruce P Bean2,*
1FM Kirby Neurobiology Research Center, Boston Children’s Hospital, Boston, United States; 2Department of Neurobiology, Harvard Medical School, Boston, United States; 3De´ partement de Pharmacologie et Physiologie, Universite´ de Montre´ al, Montre´ al, Canada; 4Department of Anesthesiology, Renaissance School of Medicine at Stony Brook University, Stony Brook, United States; 5Sage Partner International, Andover, United States
*For correspondence
†These authors contributed equally to this work
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.