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Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1.
Proc Natl Acad Sci U S A. 2008 Aug 19; 105(33):12045-50.PN

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+Show Affiliations

Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18687886

Citation

Materazzi, Serena, et al. "Cox-dependent Fatty Acid Metabolites Cause Pain Through Activation of the Irritant Receptor TRPA1." Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 33, 2008, pp. 12045-50.
Materazzi S, Nassini R, Andrè E, et al. Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A. 2008;105(33):12045-50.
Materazzi, S., Nassini, R., Andrè, E., Campi, B., Amadesi, S., Trevisani, M., Bunnett, N. W., Patacchini, R., & Geppetti, P. (2008). Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1. Proceedings of the National Academy of Sciences of the United States of America, 105(33), 12045-50. https://doi.org/10.1073/pnas.0802354105
Materazzi S, et al. Cox-dependent Fatty Acid Metabolites Cause Pain Through Activation of the Irritant Receptor TRPA1. Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):12045-50. PubMed PMID: 18687886.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1. AU - Materazzi,Serena, AU - Nassini,Romina, AU - Andrè,Eunice, AU - Campi,Barbara, AU - Amadesi,Silvia, AU - Trevisani,Marcello, AU - Bunnett,Nigel W, AU - Patacchini,Riccardo, AU - Geppetti,Pierangelo, Y1 - 2008/08/07/ PY - 2008/8/9/pubmed PY - 2008/9/17/medline PY - 2008/8/9/entrez SP - 12045 EP - 50 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 105 IS - 33 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/18687886/Cox_dependent_fatty_acid_metabolites_cause_pain_through_activation_of_the_irritant_receptor_TRPA1_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=18687886 DB - PRIME DP - Unbound Medicine ER -