- Prostaglandin J 2 inhibits inflammatory hypernociception : involvement of peripheral opioid receptor

The 15-deoxy-∆-Prostaglandin J2 (15d-PGJ2) is an endogenous ligand of peroxisome proliferator-activated receptors γ (PPAR-γ), and is now recognized as a potent antiinflammatory mediator. However, information regarding the influence of 15d-PGJ2 on inflammatory pain is still unknown. In this study, we evaluated the effect of 15d-PGJ2 upon inflammatory hypernociception and the mechanisms involved in this effect. It was observed that intraplantar administration of 15d-PGJ2 (30-300 ng/paw) inhibits the mechanical hypernociception induced by carrageenan (100 μg/paw) and by the directly acting hypernociceptive mediator, PGE2. Moreover, 15d-PGJ2 (100 ng/TMJ) inhibits formalin induced temporomandibular joint hypernociception. On the other hand, the direct administration of 15d-PGJ2 into the dorsal root ganglion, was ineffective to block PGE2induced hypernociception. In addition, the 15d-PGJ2 antinociceptive effect was enhanced by the increase of macrophage population in paw due local injection of thioglycollate, suggesting the involvement of these cells on the 15d-PGJ2-antinociceptive effect. Moreover, the antinociceptive effect of 15d-PGJ2 was also blocked by naloxone and by the PPAR-γ antagonist GW9662, suggesting the involvement of peripheral opioids and PPARγ receptor in the process. Similarly to opioids, the 15d-PGJ2 antinociceptive action depends on the nitric oxide/cGMP/PKG/KATP channel pathway since it was prevented by the pre-treatment with the inhibitors of nitric oxide synthase (L-NMMA), guanilate cyclase (ODQ), protein kinase G (KT5823) or with the ATP-sensitive potassium channel blocker (glibenclamide). Together, these results demonstrate for the first time that 15d-PGJ2 inhibits inflammatory hypernociception via PPAR-γ activation. This effect seems to be dependent on endogenous opioids and local macrophages. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on October 10, 2007 as DOI: 10.1124/jpet.107.126045 at A PE T Jornals on July 8, 2017 jpet.asjournals.org D ow nladed from