4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1.
TRPA1 is an excitatory ion channel expressed by a subpopulation of primary afferent somatosensory neurons that contain substance P and calcitonin gene-related peptide. Environmental irritants such as mustard oil, allicin, and acrolein activate TRPA1, causing acute pain, neuropeptide release, and neurogenic inflammation. Genetic studies indicate that TRPA1 is also activated downstream of one or more proalgesic agents that stimulate phospholipase C signaling pathways, thereby implicating this channel in peripheral mechanisms controlling pain hypersensitivity. However, it is not known whether tissue injury also produces endogenous proalgesic factors that activate TRPA1 directly to augment inflammatory pain. Here, we report that recombinant or native TRPA1 channels are activated by 4-hydroxy-2-nonenal (HNE), an endogenous alpha,beta-unsaturated aldehyde that is produced when reactive oxygen species peroxidate membrane phospholipids in response to tissue injury, inflammation, and oxidative stress. HNE provokes release of substance P and calcitonin gene-related peptide from central (spinal cord) and peripheral (esophagus) nerve endings, resulting in neurogenic plasma protein extravasation in peripheral tissues. Moreover, injection of HNE into the rodent hind paw elicits pain-related behaviors that are inhibited by TRPA1 antagonists and absent in animals lacking functional TRPA1 channels. These findings demonstrate that HNE activates TRPA1 on nociceptive neurons to promote acute pain, neuropeptide release, and neurogenic inflammation. Our results also provide a mechanism-based rationale for developing novel analgesic or anti-inflammatory agents that target HNE production or TRPA1 activation.
Department of Critical Care Medicine and Surgery, Florence University, 4-50121 Florence, Italy.
Marcello
M
Trevisani
Jan
J
Siemens
Serena
S
Materazzi
Diana M
DM
Bautista
Romina
R
Nassini
Barbara
B
Campi
Noritaka
N
Imamachi
Eunice
E
Andrè
Riccardo
R
Patacchini
Graeme S
GS
Cottrell
Raffaele
R
Gatti
Allan I
AI
Basbaum
Nigel W
NW
Bunnett
David
D
Julius
Pierangelo
P
Geppetti
D000171:Acrolein / Q000031:analogs & derivatives / Q000494:pharmacology; D000447:Aldehydes / Q000633:toxicity*; D017487:Ankyrins; D015220:Calcium Channels / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D003001:Cloning, Molecular; D006801:Humans; D007249:Inflammation / Q000139:chemically induced*; D010146:Pain / Q000139:chemically induced*; D018408:Patch-Clamp Techniques; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels
D000447:Aldehydes; D017487:Ankyrins; D015220:Calcium Channels; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D000171:Acrolein; C027576:4-hydroxy-2-nonenal; C012843:cinnamaldehyde