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Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception

Yingqi Weng123, Patricia A Batista-Schepman124, Marie E Barabas5, Eli Q Harris12, Thomas B Dinsmore12, Elena A Kossyreva5, Audra M Foshage12, Michelle H Wang12, Matthew J Schwab12, Victoria M Wang12, Cheryl L Stucky5 and Gina M Story12*

Author Affiliations

1 Department of Anesthesiology, Washington University Pain Center, St. Louis, MO 63110, USA

2 Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8054, St. Louis, MO 63110, USA

3 Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan, 43110, China

4 Department of Pharmacology, Center of Biological Science, Federal University of Santa Catarina, Florianopolis, SC, Brazil

5 Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

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Molecular Pain 2012, 8:75  doi:10.1186/1744-8069-8-75

Published: 27 September 2012



The Transient Receptor Potential (TRP) ion channel TRPA1 is a key player in pain pathways. Irritant chemicals activate ion channel TRPA1 via covalent modification of N-terminal cysteines. We and others have shown that 15-Deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2) similarly activates TRPA1 and causes channel-dependent nociception. Paradoxically, 15d-PGJ2 can also be anti-nociceptive in several pain models. Here we hypothesized that activation and subsequent desensitization of TRPA1 in dorsal root ganglion (DRG) neurons underlies the anti-nociceptive property of 15d-PGJ2. To investigate this, we utilized a battery of behavioral assays and intracellular Ca2+ imaging in DRG neurons to test if pre-treatment with 15d-PGJ2 inhibited TRPA1 to subsequent stimulation.


Intraplantar pre-injection of 15d-PGJ2, in contrast to mustard oil (AITC), attenuated acute nocifensive responses to subsequent injections of 15d-PGJ2 and AITC, but not capsaicin (CAP). Intraplantar 15d-PGJ2—administered after the induction of inflammation—reduced mechanical hypersensitivity in the Complete Freund’s Adjuvant (CFA) model for up to 2 h post-injection. The 15d-PGJ2-mediated reduction in mechanical hypersensitivity is dependent on TRPA1, as this effect was absent in TRPA1 knockout mice. Ca2+ imaging studies of DRG neurons demonstrated that 15d-PGJ2 pre-exposure reduced the magnitude and number of neuronal responses to AITC, but not CAP. AITC responses were not reduced when neurons were pre-exposed to 15d-PGJ2 combined with HC-030031 (TRPA1 antagonist), demonstrating that inhibitory effects of 15d-PGJ2 depend on TRPA1 activation. Single daily doses of 15d-PGJ2, administered during the course of 4 days in the CFA model, effectively reversed mechanical hypersensitivity without apparent tolerance or toxicity.


Taken together, our data support the hypothesis that 15d-PGJ2 induces activation followed by persistent inhibition of TRPA1 channels in DRG sensory neurons in vitro and in vivo. Moreover, we demonstrate novel evidence that 15d-PGJ2 is analgesic in mouse models of pain via a TRPA1-dependent mechanism. Collectively, our studies support that TRPA1 agonists may be useful as pain therapeutics.

TRPA1; 15d-PGJ2; Mustard oil; Negative modulation; Mechanical hypersensitivity