Crotalphine desensitizes TRPA1 ion channels to alleviate inflammatory hyperalgesia. Issue 11 (November 2016)

• Record Type: Journal Article
• Authors: Bressan, Elisangela; Touska, Filip; Vetter, Irina; Kistner, Katrin; Kichko, Tatjana I.; Teixeira, Nathália B.; Picolo, Gisele; Cury, Yara; Lewis, Richard J.; Fischer, Michael J.M.; Zimmermann, Katharina; Reeh, Peter W.
• Is Part Of: Pain. Volume 157:Issue 11(2016)
• Publication Date: 2016-11
• Subjects: Crotalphine -- Desensitization -- TRPA1 -- CGRP -- Ciguatoxin -- Bradykinin -- Zymosan; Pain -- Periodicals; Douleur -- Périodiques; Anesthésie -- Périodiques; Pain; Electronic journals; Periodicals; Electronic journals; 616.0472
• DOI: 10.1097/j.pain.0000000000000669
• Languages: English
• ISSNs: 0304-3959

Abstract

Abstract : Abstract: Crotalphine is a structural analogue to a novel analgesic peptide that was first identified in the crude venom from the South American rattlesnake Crotalus durissus terrificus . Although crotalphine's analgesic effect is well established, its direct mechanism of action remains unresolved. The aim of the present study was to investigate the effect of crotalphine on ion channels in peripheral pain pathways. We found that picomolar concentrations of crotalphine selectively activate heterologously expressed and native TRPA1 ion channels. TRPA1 activation by crotalphine required intact N-terminal cysteine residues and was followed by strong and long-lasting desensitization of the channel. Homologous desensitization of recombinant TRPA1 and heterologous desensitization in cultured dorsal root ganglia neurons was observed. Likewise, crotalphine acted on peptidergic TRPA1-expressing nerve endings ex vivo as demonstrated by suppression of calcitonin gene-related peptide release from the trachea and in vivo by inhibition of chemically induced and inflammatory hypersensitivity in mice. The crotalphine-mediated desensitizing effect was abolished by the TRPA1 blocker HC030031 and absent in TRPA1-deficient mice. Taken together, these results suggest that crotalphine is the first peptide to mediate antinociception selectively and at subnanomolar concentrations by targeting TRPA1 ion channels. Abstract : Supplemental Digital Content is Available in the Text.Crotalphine is the first orally bioavailable snake venom-derived peptide to selectively mediate analgesia at subnanomolar concentrations by targeting and desensitizing the TRPA1 channel.