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

Serena Materazzi, Romina Nassini, Eunice Andrè, Barbara Campi, Silvia Amadesi, Marcello Trevisani, Nigel W. Bunnett, Riccardo Patacchini, Pierangelo Geppetti

Research output: Contribution to journalArticlepeer-review

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-PGJ2, PGA 2, 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.

Original languageEnglish (US)
Pages (from-to)12045-12050
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number33
DOIs
StatePublished - Aug 19 2008

Keywords

  • Cyclopentenone isoprostane
  • Cyclopentenone prostaglandins

ASJC Scopus subject areas

  • General

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