Seungkyu Lee^1,†, Sooyeon Jo^2,†, 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 Woolf^1,2,*, Bruce P Bean^2,*

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

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.