TRPA1 contributes to cold hypersensitivity.
TRPA1 is a nonselective cation channel expressed by nociceptors. Although it is widely accepted that TRPA1 serves as a broad irritancy receptor for a variety of reactive chemicals, its role in cold sensation remains controversial. Here, we demonstrate that mild cooling markedly increases agonist-evoked rat TRPA1 currents. In the absence of an agonist, even noxious cold only increases current amplitude slightly. These results suggest that TRPA1 is a key mediator of cold hypersensitivity in pathological conditions in which reactive oxygen species and proinflammatory activators of the channel are present, but likely plays a comparatively minor role in acute cold sensation. Supporting this, cold hypersensitivity can be induced in wild-type but not Trpa1(-/-) mice by subcutaneous administration of a TRPA1 agonist. Furthermore, the selective TRPA1 antagonist HC-030031 [2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide] reduces cold hypersensitivity in rodent models of inflammatory and neuropathic pain.
Hydra Biosciences, Inc, Cambridge, Massachusetts 02139, USA. ddelcamino@hydrabiosciences.com
Donato
D
del Camino
Sarah
S
Murphy
Melissa
M
Heiry
Lee B
LB
Barrett
Taryn J
TJ
Earley
Colby A
CA
Cook
Matt J
MJ
Petrus
Michael
M
Zhao
Marc
M
D'Amours
Nate
N
Deering
Gary J
GJ
Brenner
Michael
M
Costigan
Neil J
NJ
Hayward
Jayhong A
JA
Chong
Christopher M
CM
Fanger
Clifford J
CJ
Woolf
Ardem
A
Patapoutian
Magdalene M
MM
Moran
D000818:Animals; D003080:Cold Temperature; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000502:physiology; D006930:Hyperalgesia / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009619:Nociceptors / Q000502:physiology*; D051381:Rats; D000074025:TRPA1 Cation Channel; D013697:Thermosensing / Q000502:physiology*; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse