| Summary: | <p>Abstract</p> <p>Background</p> <p>A number of prostaglandins (PGs) sensitize dorsal root ganglion (DRG) neurons and contribute to inflammatory hyperalgesia by signaling through specific G protein-coupled receptors (GPCRs). One mechanism whereby PGs sensitize these neurons is through modulation of "thermoTRPs," a subset of ion channels activated by temperature belonging to the Transient Receptor Potential ion channel superfamily. Acrid, electrophilic chemicals including cinnamaldehyde (CA) and allyl isothiocyanate (AITC), derivatives of cinnamon and mustard oil respectively, activate thermoTRP member TRPA1 via direct modification of channel cysteine residues.</p> <p>Results</p> <p>Our search for endogenous chemical activators utilizing a bioactive lipid library screen identified a cyclopentane PGD<sub>2 </sub>metabolite, 15-deoxy-Δ<sup>12,14</sup>-prostaglandin J<sub>2 </sub>(15d-PGJ<sub>2</sub>), as a TRPA1 agonist. Similar to CA and AITC, this electrophilic molecule is known to modify cysteines of cellular target proteins. Electophysiological recordings verified that 15d-PGJ<sub>2 </sub>specifically activates TRPA1 and not TRPV1 or TRPM8 (thermoTRPs also enriched in DRG). Accordingly, we identified a population of mouse DRG neurons responsive to 15d-PGJ<sub>2 </sub>and AITC that is absent in cultures derived from TRPA1 knockout mice. The irritant molecules that activate TRPA1 evoke nociceptive responses. However, 15d-PGJ<sub>2 </sub>has not been correlated with painful sensations; rather, it is considered to mediate anti-inflammatory processes via binding to the nuclear peroxisome proliferator-activated receptor gamma (PPARγ). Our <it>in vivo </it>studies revealed that 15d-PGJ<sub>2 </sub>induced acute nociceptive responses when administered cutaneously. Moreover, mice deficient in the TRPA1 channel failed to exhibit such behaviors.</p> <p>Conclusion</p> <p>In conclusion, we show that 15d-PGJ<sub>2 </sub>induces acute nociception when administered cutaneously and does so via a TRPA1-specific mechanism.</p>
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