TY - JOUR TI - Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation AU - Lee, Seungkyu AU - Jo, Sooyeon AU - Talbot, Sébastien AU - Zhang, Han-Xiong Bear AU - Kotoda, Masakazu AU - Andrews, Nick A AU - Puopolo, Michelino AU - Liu, Pin W AU - Jacquemont, Thomas AU - Pascal, Maud AU - Heckman, Laurel M AU - Jain, Aakanksha AU - Lee, Jinbo AU - Woolf, Clifford J AU - Bean, Bruce P A2 - Swartz, Kenton J A2 - Aldrich, Richard W A2 - Swartz, Kenton J A2 - Lipscombe, Diane VL - 8 PY - 2019 DA - 2019/11/25 SP - e48118 C1 - eLife 2019;8:e48118 DO - 10.7554/eLife.48118 UR - https://doi.org/10.7554/eLife.48118 AB - 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. KW - Cav2.2 KW - calcitonin gene-related peptide KW - inflammatory peptide KW - asthma KW - Nav1.7 KW - dorsal root ganglion JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -