Secondary Logo

Journal Logo

Institutional members access full text with Ovid®

Crotalphine desensitizes TRPA1 ion channels to alleviate inflammatory hyperalgesia

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.

doi: 10.1097/j.pain.0000000000000669
Research Paper

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.

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.

aInstitute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nurnberg, Erlangen, Germany

bDepartment of Physiology, University Hospital RWTH Aachen, Aachen, Germany

cDepartment of Cellular Neurophysiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic

dInstitute for Molecular Bioscience, The University of Queensland, St. Lucia, Australia

eLaboratory of Pain and Signaling, Butantan Institute, São Paulo, Brazil

fDepartment of Anesthesiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nurnberg, Erlangen, Germany

Corresponding author. Address: Department of Physiology, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany. Tel.: (+49) 241 80 88820; fax: (+49) 241 80 82434. E-mail address: (E. Bressan).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Received March 04, 2016

Received in revised form June 23, 2016

Accepted July 11, 2016

© 2016 International Association for the Study of Pain
You currently do not have access to this article

To access this article:

Note: If your society membership provides full-access, you may need to login on your society website