15d-prostaglandin J2 inhibits inflammatory hypernociception: involvement of peripheral opioid receptor.
The 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is an endogenous ligand of peroxisome proliferator-activated receptors gamma (PPAR-gamma) and is now recognized as a potent anti-inflammatory mediator. However, information regarding the influence of 15d-PGJ(2) on inflammatory pain is still unknown. In this study, we evaluated the effect of 15d-PGJ(2) upon inflammatory hypernociception and the mechanisms involved in this effect. We observed that intraplantar administration of 15d-PGJ(2) (30-300 ng/paw) inhibits the mechanical hypernociception induced by both carrageenan (100 mug/paw) and the directly acting hypernociceptive mediator, prostaglandin E(2) (PGE(2)). Moreover, 15d-PGJ(2) [100 ng/temporomandibular joint (TMJ)] inhibits formalin-induced TMJ hypernociception. On the other hand, the direct administration of 15d-PGJ(2) into the dorsal root ganglion was ineffective in blocking PGE(2)-induced hypernociception. In addition, the 15d-PGJ(2) 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-PGJ(2)-antinociceptive effect. Moreover, the antinociceptive effect of 15d-PGJ(2) was also blocked by naloxone and by the PPAR-gamma antagonist 2-chloro-5-nitro-N-phenylbenzamide (GW9662), suggesting the involvement of peripheral opioids and PPAR-gamma receptor in the process. Similar to opioids, the 15d-PGJ(2) antinociceptive action depends on the nitric oxide/cGMP/protein kinase G (PKG)/K(ATP)(+) 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-alpha)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-PGJ(2) inhibits inflammatory hypernociception via PPAR-gamma activation. This effect seems to be dependent on endogenous opioids and local macrophages.
Napimoga
Marcelo H
MH
Laboratory of Molecular Biology, University of Uberaba, Av. Nenê Sabino, 1801, Uberaba, Minas Gerais 38055-500, Brazil. marcelo.napimoga@uniube.br
Souza
Guilherme R
GR
Cunha
Thiago M
TM
Ferrari
Luiz F
LF
Clemente-Napimoga
Juliana T
JT
Parada
Carlos A
CA
Verri
Waldiceu A
WA
Cunha
Fernando Q
FQ
Ferreira
Sérgio H
SH
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002351:Carrageenan; D016207:Cytokines / Q000276:immunology; D005557:Formaldehyde; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists; D047495:PPAR gamma / Q000276:immunology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000276:immunology*; D012867:Skin / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha
C477819:15-deoxyprostaglandin J2; D000700:Analgesics; D016207:Cytokines; D009292:Narcotic Antagonists; D047495:PPAR gamma; D011957:Receptors, Opioid; D014409:Tumor Necrosis Factor-alpha; D005557:Formaldehyde; D009270:Naloxone; D002351:Carrageenan; D015230:Prostaglandin D2