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BEHAVIORAL PHARMACOLOGY

15d-Prostaglandin J₂ Inhibits Inflammatory Hypernociception: Involvement of Peripheral Opioid Receptor

Laboratory of Molecular Biology, University of Uberaba, Uberaba, Brazil (M.H.N., J.T.C.-N.); and Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil (M.H.N., G.R.S., T.M.C., L.F.F., C.A.P., W.A.V., F.Q.C., S.H.F.)

The 15-deoxy-^12,14-prostaglandin J₂ (15d-PGJ₂) is an endogenous ligand of peroxisome proliferator-activated receptors (PPAR-) and is now recognized as a potent anti-inflammatory 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. We observed that intraplantar administration of 15d-PGJ₂ (30–300 ng/paw) inhibits the mechanical hypernociception induced by both carrageenan (100 µg/paw) and the directly acting hypernociceptive mediator, prostaglandin E₂ (PGE₂). Moreover, 15d-PGJ₂ [100 ng/temporomandibular joint (TMJ)] inhibits formalin-induced TMJ hypernociception. On the other hand, the direct administration of 15d-PGJ₂ into the dorsal root ganglion was ineffective in blocking PGE₂-induced hypernociception. In addition, the 15d-PGJ₂ antinociceptive effect was enhanced by the increase of macrophage population in paw tissue due to 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- antagonist 2-chloro-5-nitro-N-phenylbenzamide (GW9662), suggesting the involvement of peripheral opioids and PPAR- receptor in the process. Similar to opioids, the 15d-PGJ₂ antinociceptive action depends on the nitric oxide/cGMP/protein kinase G channel pathway because it was prevented by the pretreatment with the inhibitors of nitric-oxide synthase (N^G-monomethyl-L-arginine acetate), guanylate cyclase]1H-(1,2,4)-oxadiazolo(4,2-)quinoxalin-1-one[, PKG [indolo[2,3-a]pyrrolo[3,4-c]carbazole aglycone (KT5823)], or with the ATP-sensitive potassium channel blocker glibenclamide. Taken together, these results demonstrate for the first time that 15d-PGJ₂ inhibits inflammatory hypernociception via PPAR- activation. This effect seems to be dependent on endogenous opioids and local macrophages.

Address correspondence to: Dr. Marcelo H. Napimoga, Laboratory of Molecular Biology, University of Uberaba, Av. Nenê Sabino, 1801, Uberaba, Minas Gerais 38055-500, Brazil. E-mail: marcelo.napimoga{at}uniube.br

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