Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception

• Main Authors: Weng Yingqi, Batista-Schepman Patricia A, Barabas Marie E, Harris Eli Q, Dinsmore Thomas B, Kossyreva Elena A, Foshage Audra M, Wang Michelle H, Schwab Matthew J, Wang Victoria M, Stucky Cheryl L, Story Gina M
• Format: Article
• Language: English
• Published: SAGE Publishing 2012-09-01
• Series: Molecular Pain
• Subjects: TRPA1; 15d-PGJ₂; Mustard oil; Negative modulation; Mechanical hypersensitivity
• Online Access: http://www.molecularpain.com/content/8/1/75

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>Taken together, our data support the hypothesis that 15d-PGJ₂ induces activation followed by persistent inhibition of TRPA1 channels in DRG sensory neurons <it>in vitro</it> and <it>in vivo</it>. 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.</p>