期刊
PAIN
卷 157, 期 11, 页码 2504-2516出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/j.pain.0000000000000669
关键词
Crotalphine; Desensitization; TRPA1; CGRP; Ciguatoxin; Bradykinin; Zymosan
资金
- Brazilian National Council for Scientific and Technological Development-CNPq
- B. Braun Foundation Melsungen
- Johannes and Frieda Marohn-Foundation
- German Research Council (DFG) [Zi 1172/2-1]
- Fresenius Foundation
- Australian Research Council ARC LIEF grant for the FLIPRTetra
- National Health and Medical Research Council Grant
- Sao Paulo Research Foundation-FAPESP
- INCTTOX (FAPESP) [08/57898-0]
- CNPq [573790/2008-6]
- CEPID/FAPESP program [1998/14307-9, 2013/07467-1]
- BAYLAT/FAPESP initiative [2012/51458-4]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [08/57898-0] Funding Source: FAPESP
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.
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