Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 33; pp. 12045 - 12050
• Main Authors: Materazzi, Serena, Nassini, Romina, Andrè, Eunice, Campi, Barbara, Amadesi, Silvia, Trevisani, Marcello, Bunnett, Nigel W, Patacchini, Riccardo, Geppetti, Pierangelo
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19-08-2008; National Acad Sciences
• Subjects: Animals; Biological Sciences; Calcium; Calcium - metabolism; Fatty acids; Fatty Acids - metabolism; Ganglia, Spinal - metabolism; Inflammation; Inflammatory diseases; Isoprostanes; Mice; Mice, Knockout; Neurons; Neurons - metabolism; Nociceptors; Nociceptors - metabolism; Pain; Pain - genetics; Pain - metabolism; Prostaglandin-Endoperoxide Synthases - metabolism; Prostaglandins; Rats; Receptors; Rodents; Spinal cord; Tissue Culture Techniques; Transient Receptor Potential Channels - deficiency; Transient Receptor Potential Channels - genetics; Transient Receptor Potential Channels - metabolism; TRPA1 Cation Channel
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0802354105

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-PGJ₂, PGA₂, and PGA₁, formed by dehydration of their respective parent PGs, PGD₂, PGE₂, and PGE₁, possess a highly reactive α,β-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, PGE₂, 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.