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Cox-Dependent Fatty Acid Metabolites Cause Pain Through Activation of the Irritant Receptor TRPA1

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Cox-Dependent Fatty Acid Metabolites Cause Pain Through Activation of the Irritant Receptor TRPA1 Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1 Serena Materazzi*, Romina Nassini*, Eunice Andre` †, Barbara Campi†, Silvia Amadesi‡, Marcello Trevisani†, Nigel W. Bunnett‡, Riccardo Patacchini§, and Pierangelo Geppetti*†¶ *Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy; †Center of Excellence for the Study of Inflammation, University of Ferrara, Ferrara, Italy; ‡Departments of Surgery and Physiology, University of California, San Francisco, CA 94143; and §Pharmacology Department, Chiesi Pharmaceuticals, Parma, Italy Edited by Susan E. Leeman, Boston University School of Medicine, Boston, MA, and approved June 6, 2008 (received for review March 8, 2008) Prostaglandins (PG) are known to induce pain perception indirectly EP1–4 and IP receptors, respectively (7–9). Accordingly, the by sensitizing nociceptors. Accordingly, the analgesic action of analgesic property of NSAIDs and selective COX-2 inhibitors nonsteroidal anti-inflammatory drugs (NSAIDs) results from inhi- (Coxibs) has been assigned to their ability to suppress nociceptor bition of cyclooxygenases and blockade of PG biosynthesis. Cyclo- sensitization by COX metabolites (7–9). pentenone PGs, 15-d-PGJ2, PGA2, and PGA1, formed by dehydration Transient receptor potential A1 (TRPA1) is a recently iden- tified excitatory ion channel (10, 11) that is coexpressed with the of their respective parent PGs, PGD2, PGE2, and PGE1, possess a highly reactive ␣,␤-unsaturated carbonyl group that has been ‘‘capsaicin receptor’’ TRPV1 by a subpopulation of primary proposed to gate the irritant transient receptor potential A1 afferent neurons containing substance P (SP) and calcitonin gene-related peptide (CGRP), which mediate pain and neuro- TRPA1) channel. Here, by using TRPA1 wild-type (TRPA1؉/؉)or) ؊/؊ genic inflammation (12–15). Agonists of TRPA1 include the deficient (TRPA1 ) mice, we show that cyclopentenone PGs pungent ingredients of various spices, including mustard, garlic, produce pain by direct stimulation of nociceptors via TRPA1 acti- and cinnamon (11, 16), environmental irritants such as acrolein vation. Cyclopentenone PGs caused a robust calcium response in ؉ ؉ (14), formaldehyde (17), and 4-hydroxy-2-nonenal (4-HNE), an dorsal root ganglion (DRG) neurons of TRPA1 / , but not of endogenous ␣,␤-unsaturated aldehyde generated in response to .(TRPA1؊/؊ mice, and a calcium-dependent release of sensory neu- oxidative stress after inflammation and tissue injury (18, 19 ropeptides from the rat dorsal spinal cord. Intraplantar injection of Cyclopentenone prostaglandins, including PGA2, PGA1, and PHARMACOLOGY cyclopentenone PGs stimulated c-fos expression in spinal neurons PGJ2, are PG metabolites formed by dehydration within the of the dorsal horn and evoked an instantaneous, robust, and cyclopentane ring of PGE2, PGE1, and PGD2, respectively. The transient nociceptive response in TRPA1؉/؉ but not in TRPA1؊/؊ biological actions of cyclopentenone PGs are not mediated by mice. The classical proalgesic PG, PGE2, caused a slight calcium activation of the classical G protein-coupled prostanoid receptors, response in DRG neurons, increased c-fos expression in spinal neu- but rather through interaction with other target proteins (20). For ⌬12,14 rons, and induced a delayed and sustained nociceptive response in example, 15-deoxy- -PGJ2 (15-d-PGJ2), a PGJ2 metabolite, is ؉/؉ ؊/؊ a potent natural activator of the nuclear receptor peroxisome both TRPA1 and TRPA1 mice. These results expand the mech- ␥ anism of NSAID analgesia from blockade of indirect nociceptor sen- proliferator-activated receptor (PPAR)- (20). Cyclopentenone PGs are characterized by the presence of a highly reactive ␣,␤- sitization by classical PGs to inhibition of direct TRPA1-dependent unsaturated carbonyl group within their cyclopentenone ring, a nociceptor activation by cyclopentenone PGs. Thus, TRPA1 antago- moiety that confers the ability to adduct thiol-containing com- nism may contribute to suppress pain evoked by PG metabolites pounds, via Michael addition (20), and through this mechanism without the adverse effects of inhibiting cyclooxygenases. they have been proposed to stimulate TRPA1 (21). We hypothesized that cyclopentenone PGs stimulate TRPA1 cyclopentenone isoprostane ͉ cyclopentenone prostaglandins and thereby directly activate nociceptors to cause pain, in contrast to the classical PGs that indirectly sensitize nociceptors. rostanoids are a group of bioactive compounds that include We have obtained genetic evidence that cyclopentenone PGs excite nociceptors, release sensory neuropeptides, activate spinal Pprostaglandins (PGD2, PGE2, PGF2␣), prostacyclin (PGI2), and thromboxane A . They originate from arachidonic acid, nociceptive neurons, and induce acute pain by a mechanism that 2 is completely and exclusively dependent on TRPA1. Cyclopen- which is released intracellularly from plasma membrane phos- tenone PGs may represent a new class of COX-dependent algesic pholipids upon tissue damage and inflammation. Constitutively agents, and their novel mechanism of action adds a new dimen- expressed cyclooxygenase (COX)-1 and inducible COX-2 con- sion to our understanding of the mechanisms of the analgesic vert arachidonic acid to the precursors PGG2 and PGH2, from effect of NSAIDs and Coxibs. which all prostanoids are generated by tissue-specific synthases. The C20 polyunsaturated fatty acid, dihomo-␥-linolenic acid, is Results also a substrate of COX for eicosanoid production, from which Cyclopentenone PGs Activate TRPA1 in Dorsal Root Ganglion (DRG) prostaglandins of the 1-series, including PGE1, derive (1). Inhi- Neurons. To assess whether cyclopentenone PGs directly excite bition of COX activity is the main mechanism of action of aspirin DRG neurons by a TRPA1-dependent mechanism, we tested the and related nonsteroidal anti-inflammatory drugs (NSAIDs), as discovered by the pioneering work of Vane and colleagues (2). At least eight G protein-coupled receptor subtypes for prosta- Author contributions: N.W.B., R.P., and P.G. designed research; S.M., R.N., E.A., B.C., S.A., and M.T. performed research; S.M., R.N., E.A., B.C., S.A., M.T., N.W.B., R.P., and P.G. noids have been identified, which differ in tissue distribution, analyzed data; and N.W.B., R.P., and P.G. wrote the paper. signal transduction pathways, and sensitivity to the various The authors declare no conflict of interest. agonists (3, 4). This article is a PNAS Direct Submission. Pain relief, by far, is the most frequent therapeutic indication ¶To whom correspondence should be addressed at: Department of Preclinical and Clinical of COX inhibitors, and the contribution of prostanoids and their Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. E-mail: receptors to pain has been an area of intense investigation (5, 6). pierangelo.geppetti@unifi.it. PGs do not directly excite primary sensory neurons but rather This article contains supporting information online at www.pnas.org/cgi/content/full/ indirectly sensitize the peripheral terminals of nociceptors, with 0802354105/DCSupplemental. PGE2 and PGI2 inducing a robust sensitization by activating © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0802354105 PNAS ͉ August 19, 2008 ͉ vol. 105 ͉ no. 33 ͉ 12045–12050 Downloaded by guest on September 24, 2021 2ϩ Fig. 1. Cyclopentenone PGs and isoprostane increase [Ca ]i in mouse DRG neurons. (A) Concentration-response curves of cyclopentenone PGs or isoprostane and 2ϩ PGE2 in DRG neurons of Swiss mice (n ϭ 521 neurons). (B) Representative traces of [Ca ]i evoked by 15-d-PGJ2 (30 ␮M) or PGE2 (30 ␮M), followed by capsaicin (CPS, ϩ/ϩ Ϫ/Ϫ 1 ␮M) and potassium (KCl, 50 mM). A calcium response was induced by 15-d-PGJ2 in DRG neurons from TRPA1 but not from TRPA1 mice. PGE2, capsaicin or ϩ/ϩ Ϫ/Ϫ 2ϩ potassium evoked a similar response in neurons from TRPA1 or TRPA1 mice. (C) Pooled data of [Ca ]i evoked by cinnamaldehyde (CNM, 30 ␮M), capsaicin (1 ␮M), ϩ/ϩ Ϫ/Ϫ 15-d-PGJ2, PGA1, PGA2, 8-iso-PGA2, PGD2, and PGE2 (all 30 ␮M) in DRG neurons from TRPA1 (gray or orange columns) or TRPA1 (filled or red columns) mice. Among CPS-sensitive neurons from wild-type animals, a subpopulation of CNM-responsive cells was observed. In DRG neurons from TRPA1-deficient mice CNM, 15-d-PGJ2, ϩ/ϩ Ϫ/Ϫ PGA1, PGA2, or 8-iso-PGA2 did not cause any response. PGE2 evoked a small response in DRG neurons from TRPA1 or TRPA1 mice. PGD2 failed to cause any response. ϩ ϩ Ϫ Ϫ The robust response evoked by capsaicin was similar in neurons from TRPA1 / and TRPA1 / mice. Each column represents the mean Ϯ SEM of n Ն 23 cells; *, P Ͻ 0.01 compared with TRPA1Ϫ/Ϫ DRG neurons. Ϫ/Ϫ ability of 15-d-PGJ2, PGA2, and PGA1 to mobilize intracellular neurons from TRPA1 mice were almost completely unrespon- 2ϩ calcium ([Ca ]i) in DRG neurons from Swiss mice and from sive to 15-d-PGJ2, PGA2, PGA1, and 8-iso-PGA2 (Fig. 1 B and C), TRPA1 wild-type (TRPA1ϩ/ϩ) and deficient (TRPA1Ϫ/Ϫ) mice. and the ratio between the number of neurons responding to We also evaluated the effects of the isoprostane, 8-iso-PGA2, cyclopentenone compounds (30 ␮M) and neurons responding to which can also stimulate TRPA1 (21). Isoprostanes are PG-like capsaicin was: PGA2 (2/34, 5%), PGA1 (3/46, 2%), 15-d-PGJ2 (2/30, substances whose generation does not require COX activation 6%), and 8-iso-PGA2 (3/48, 6%). Moreover, the magnitude of the 2ϩ Ϫ/Ϫ (22). A cyclopentenone isoprostane isomer of PGA2, 8-iso- increase in [Ca ]i in the few neurons from TRPA1 mice that PGA2, like cyclopentenone PGs, is produced by dehydration of responded to cyclopentenone compounds was always Ͻ5% of that ϩ/ϩ E-isoprostane within the cyclopentane ring. It (8-iso-PGA2) of ionomycin, whereas responses of neurons from TRPA1 mice contains an electrophilic ␣,␤-unsaturated carbonyl moiety that were 30–50% of the ionomycin response (Fig. 1C). No response to ϩ/ϩ rapidly adducts cellular thiols by Michael addition (23). PGD2 was observed in neurons from either TRPA1 or Ϫ/Ϫ 15-d-PGJ2, PGA2, PGA1, and 8-iso-PGA2 evoked a concen- TRPA1 mice (Fig.
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