The Effect Of 15d-PGJ₂ To TRPA1 And The Inhibition To TRPA1-mediated Pain

Transient receptor potential ion channels (TRPs) are recently founded non-selective cation channels which exist in plasmic membrane. The subtype TRPA1 was found mediating the sensation of cold, irritant chemicals and mechanical stimulus, it is also underlying the mechanism of inflammatory and neuropathic pain.Newly found prostaglandin 15-deoxy-A 12,14-prostaglandin J2 (15d-PGJ2) is expressed when tissue is undergoing injury, inflammation or oxidative stress. We and others have shown that 15d-PGJ2can activate ion channel TRPA1 via covalent modification of N-terminal cysteines and causes channel-dependent nocifensive behavior. Paradoxically, recent studies indicate that 15d-PGJ2 is anti-nociceptive in several pain models.We hypothesized that activation and subsequent desensitization of TRPA1 in peripheral sensory neurons might play a role in the anti-nociceptive property of 15d-PGJ2. To investigate this, we initially utilized Fura-2AM calcium imaging to test the activation of DRG neurons with different doses of 15d-PGJ2 and AITC, their nociceptive effect was observed as well. Then, compared to pre-exposure to allyl isothiocyanate (AITC, mustard oil), we tested whether pre-treatment with 15d-PGJ2 could desensitize TRPA1-expressing dorsal root ganglion (DRG) neurons and inhibit nociceptive behaviors to subsequent stimulation. Finally, we tested if intraplantar pre-injection of 15d-PGJ2 could reduce mechanical hypersensitivity in the Complete Freund's Adjuvant model, and whether TRPA1 was involved in the analgesic mechanism of 15d-PGJ2. The results were as followed:1.15d-PGJ2 and AITC activated DRG neurons and caused nociceptive behaviors in a dose-dependent manner.15d-PGJ2 of a concentration higher than saturated one caused decresed nociceptive response.2. We found that pre-exposure 15d-PGJ2 reduced the magnitude and number of subsequent responses to AITC, but not capsaicin (CAP). A series of analogous behavioral studies demonstrated that intraplantar pre-injection of 15d-PGJ2, in contrast to AITC, attenuated acute nocifensive responses to subsequent injections of 15d-PGJ2 and AITC, but not CAP.3. Intraplantar 15d-PGJ2-administered after the induction of inflammation-also reduced mechanical hypersensitivity in the Complete Freund's Adjuvant (CFA) model for up to 2 hours post-injection. The 15d-PGJ2-mediated reduction in mechanical hypersensitivity was dependent on TRPA1, as this effect was absent in TRPA1 knockout mice.In conclusion, our data supports the hypothesis that 15d-PGJ2 induces activation followed by persistent desensitization of TRPA1 channels expressed in peripheral sensory neurons both in vitro and in vivo. Whether this is a unique property of TRPA1 modulation by 15d-PGJ2 merits further investigation.