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Crotalphine desensitizes TRPA1 ion channels to alleviate inflammatory hyperalgesia.
- Source :
-
Pain [Pain] 2016 Nov; Vol. 157 (11), pp. 2504-2516. - Publication Year :
- 2016
-
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.
- Subjects :
- Action Potentials drug effects
Analgesics pharmacology
Animals
Bradykinin toxicity
Calcium metabolism
Cells, Cultured
Disease Models, Animal
Ganglia, Spinal cytology
HEK293 Cells
Humans
Hyperalgesia chemically induced
Hyperalgesia etiology
Inflammation complications
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation genetics
Neurons drug effects
Neurons metabolism
Peptides pharmacology
TRPA1 Cation Channel
Transient Receptor Potential Channels antagonists & inhibitors
Transient Receptor Potential Channels genetics
Zymosan toxicity
Analgesics therapeutic use
Hyperalgesia drug therapy
Peptides therapeutic use
Transient Receptor Potential Channels metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1872-6623
- Volume :
- 157
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Pain
- Publication Type :
- Academic Journal
- Accession number :
- 27434506
- Full Text :
- https://doi.org/10.1097/j.pain.0000000000000669