Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling

Ciguatoxins are sodium channel activator toxins that cause ciguatera, the most common form of ichthyosarcotoxism, which presents with peripheral sensory disturbances, including the pathognomonic symptom of cold allodynia which is characterized by intense stabbing and burning pain in response to mild...

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Bibliographic Details
Published in:The EMBO journal 2012-10, Vol.31 (19), p.3795-3808
Main Authors: Vetter, Irina, Touska, Filip, Hess, Andreas, Hinsbey, Rachel, Sattler, Simon, Lampert, Angelika, Sergejeva, Marina, Sharov, Anastasia, Collins, Lindon S, Eberhardt, Mirjam, Engel, Matthias, Cabot, Peter J, Wood, John N, Vlachová, Viktorie, Reeh, Peter W, Lewis, Richard J, Zimmermann, Katharina
Format: Article
Language:English
Subjects:
Animals
Calcium
Ciguatera
Ciguatoxin
Ciguatoxins - toxicity
Cold
cold allodynia
Cold Temperature
Food contamination & poisoning
Hyperalgesia - chemically induced
Magnetic Resonance Imaging
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Nav
Neurons
nociceptor
Oxygenation
Pain - chemically induced
Pathology
Rats
Rats, Wistar
Sensory Receptor Cells - drug effects
Signal Transduction - drug effects
Symptoms
Toxicants
Toxicology
Transient Receptor Potential Channels - drug effects
Transient Receptor Potential Channels - genetics
TRPA1
TRPA1 Cation Channel
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Summary:Ciguatoxins are sodium channel activator toxins that cause ciguatera, the most common form of ichthyosarcotoxism, which presents with peripheral sensory disturbances, including the pathognomonic symptom of cold allodynia which is characterized by intense stabbing and burning pain in response to mild cooling. We show that intraplantar injection of P‐CTX‐1 elicits cold allodynia in mice by targeting specific unmyelinated and myelinated primary sensory neurons. These include both tetrodotoxin‐resistant, TRPA1‐expressing peptidergic C‐fibres and tetrodotoxin‐sensitive A‐fibres. P‐CTX‐1 does not directly open heterologously expressed TRPA1, but when co‐expressed with Nav channels, sodium channel activation by P‐CTX‐1 is sufficient to drive TRPA1‐dependent calcium influx that is responsible for the development of cold allodynia, as evidenced by a large reduction of excitatory effect of P‐CTX‐1 on TRPA1‐deficient nociceptive C‐fibres and of ciguatoxin‐induced cold allodynia in TRPA1‐null mutant mice. Functional MRI studies revealed that ciguatoxin‐induced cold allodynia enhanced the BOLD (Blood Oxygenation Level Dependent) signal, an effect that was blunted in TRPA1‐deficient mice, confirming an important role for TRPA1 in the pathogenesis of cold allodynia. Ciguatoxins derived from fish lead to cold allodynia in humans, the perception of intense burning pain in response to mild cooling. A novel mouse model of ciguatoxin‐induced cold allodynia reveals that ciguatoxin activates the TRPA1 thermosensitive ion channel to mediate pain perception.
ISSN:0261-4189
1460-2075
DOI:10.1038/emboj.2012.207