title: Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1.
abstract: Prostaglandins (PG) are known to induce pain perception indirectly by sensitizing nociceptors. Accordingly, the analgesic action of nonsteroidal anti-inflammatory drugs (NSAIDs) results from inhibition of cyclooxygenases and blockade of PG biosynthesis. Cyclopentenone PGs, 15-d-PGJ(2), PGA(2), and PGA(1), formed by dehydration of their respective parent PGs, PGD(2), PGE(2), and PGE(1), possess a highly reactive alpha,beta-unsaturated carbonyl group that has been proposed to gate the irritant transient receptor potential A1 (TRPA1) channel. Here, by using TRPA1 wild-type (TRPA1(+/+)) or deficient (TRPA1(-/-)) mice, we show that cyclopentenone PGs produce pain by direct stimulation of nociceptors via TRPA1 activation. Cyclopentenone PGs caused a robust calcium response in dorsal root ganglion (DRG) neurons of TRPA1(+/+), but not of TRPA1(-/-) mice, and a calcium-dependent release of sensory neuropeptides from the rat dorsal spinal cord. Intraplantar injection of cyclopentenone PGs stimulated c-fos expression in spinal neurons of the dorsal horn and evoked an instantaneous, robust, and transient nociceptive response in TRPA1(+/+) but not in TRPA1(-/-) mice. The classical proalgesic PG, PGE(2), caused a slight calcium response in DRG neurons, increased c-fos expression in spinal neurons, and induced a delayed and sustained nociceptive response in both TRPA1(+/+) and TRPA1(-/-) mice. These results expand the mechanism of NSAID analgesia from blockade of indirect nociceptor sensitization by classical PGs to inhibition of direct TRPA1-dependent nociceptor activation by cyclopentenone PGs. Thus, TRPA1 antagonism may contribute to suppress pain evoked by PG metabolites without the adverse effects of inhibiting cyclooxygenases.
authors.affiliation: Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Materazzi
authors.forename: Romina
authors.initials: R
authors.lastname: Nassini
authors.forename: Eunice
authors.initials: E
authors.lastname: Andrè
authors.forename: Barbara
authors.initials: B
authors.lastname: Campi
authors.forename: Silvia
authors.initials: S
authors.lastname: Amadesi
authors.forename: Marcello
authors.initials: M
authors.lastname: Trevisani
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
authors.forename: Riccardo
authors.initials: R
authors.lastname: Patacchini
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Geppetti
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism; D010146:Pain / Q000235:genetics / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D000074025:TRPA1 Cation Channel; D046509:Tissue Culture Techniques; D050051:Transient Receptor Potential Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D011451:Prostaglandin-Endoperoxide Synthases; D002118:Calcium