Abstract
Nitro-oleic acid (NO(2)-OA) and related nitroalkenes are electrophilic fatty acid derivatives that are present in normal tissues at nanomolar concentrations and can increase significantly during inflammation. These substances can suppress multiple intracellular signaling pathways contributing to inflammation by reversible Michael addition reactions with nucleophilic residues such as cysteine and histidine leading to post-translational modification of proteins. NO(2)-OA also can influence inflammation and pain by acting on transient receptor potential (TRP) channels in primary sensory neurons. TRPV1, TRPA1 and TRPC can respond to electrophilic fatty acids because they have ankyrin-like repeats in their N terminus that are rich in cysteine residues that react with electrophiles and other thiol modifying species. NO(2)-OA acts on TRP channels to initially depolarize and induce firing in sensory neurons followed by desensitization and suppression of firing. In vivo experiments revealed that pretreatment with NO(2)-OA reduces nociceptive behavior evoked by local administration of a TRPA1 agonist (AITC) to the rat hind paw. These results raise the possibility that NO(2)-OA might be useful clinically to reduce neurogenic inflammation and certain types of painful sensations by desensitizing TRPA1 expressing nociceptive afferents.