4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1

Abstract

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 ␣,␤-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.oxidative stress ͉ sensory signaling ͉ TRP channel ͉ nociception

A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma

“…Potential endogenous TRPA1 agonists include reactive oxygen species, hypochlorite, and lipid peroxidation products (18,(24)(25)(26). Similar to TRPV1, TRPA1 is activated or sensitized downstream of inflammatory PLC-coupled receptor pathways and mediates inflammatory pain sensitization (12)(13)(14)27).…”

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

“…Most of TRPA1 activators are characterized by the presence of a highly reactive electrophilic group that, via a Michael-addition reaction, form covalent bonds with nucleophilic groups, such as cysteine and lysine residues located in the N-terminal cytoplasmic domain of the channel, hence inducing modifications of TRPA1 N-terminal that lead to dilation of the channel permeation pore [141,142]. As in the case of electrophilic agonists, HNE provokes TRPA1 gating by covalent modification of cysteine and lysine residues located within the N-terminal cytoplasmic domain of the channel [138]. Unlike these molecular species, it has been reported that H 2 O 2 activates TRPA1 via disulfide bond formation induced by oxidation [143].…”

“…Oxidative decomposition of polyunsaturated fatty acids, such as linoleic and arachidonic acid, leads to the formation of a host of reactive carbonyl species that may target TRPA1. These products include , -unsaturated aldehydes acrolein, 4-hydroxy-2-nonenal (HNE) [138], and 4-oxononenal [139]. Moreover, reactive nitrogen species (RNS) such as peroxynitrite and nitrooleic acid [130] and ROS, such as oxygen peroxide and hydrogen peroxide [140], target TRPA1.…”

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

“…(33) ree of the TRP group of receptors have been shown to be stimulated by increased superoxide and/or oxidative stress or their downstream consequences, these being the TRPV1, TRPA1, and TRPM2 receptors, with the increased TRPV1, and TRPA1 activity being produced in part through the oxidation of cysteine residue side chains [70][71][72][73][74]. Several TRP receptors are also activated by nitric oxide-mediated nitrosylation [75].…”