Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1.
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.
Materazzi
Serena
S
Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.
Nassini
Romina
R
Andrè
Eunice
E
Campi
Barbara
B
Amadesi
Silvia
S
Trevisani
Marcello
M
Bunnett
Nigel W
NW
Patacchini
Riccardo
R
Geppetti
Pierangelo
P
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*
D005227:Fatty Acids; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D011451:Prostaglandin-Endoperoxide Synthases; D002118:Calcium