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

Abstract

The 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) 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-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 g/paw) and the directly acting hypernociceptive mediator, prostaglandin E 2 (PGE 2 ). Moreover, 15d-PGJ 2 [100 ng/temporomandibular joint (TMJ)] inhibits formalininduced 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-␥ antagonist 2-chloro-5-nitro-Nphenylbenzamide (GW9662), suggesting the involvement of peripheral opioids and PPAR-␥ 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 ϩ 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,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-␥ activation. This effect seems to be dependent on endogenous opioids and local macrophages.

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…Other cyclopentenone prostanoids that contain one or two electrophilic carbons (12-PGJ 2 , 8-iso PGA 2 , PGA 2, PGA 1 ) mimicked the TRPA1-activating effect of 15dPGJ 2 , whereas their structurally related precursors lacking electrophilic carbons (PGD 2 , PGE 2 ) failed to do so, indicating the importance of electrophilic moieties for TRPA1 activation (474,715). It is worth mentioning, however, that 15dPGJ 2 has been reported to inhibit carrageenan-or PGE 2 -induced mechanical hyperalgesia and formalin-evoked overt nociception (528,566). It was proposed that 15dPGJ 2 activated opioid peptide-expressing macrophages via peroxisome proliferator-activated receptor gamma receptors and that the released opioids then produced local antinociception.…”

15d-PGJ2-loaded in nanocapsules enhance the antinociceptive properties into rat temporomandibular hypernociception

“…Pharmacological activation of PPAR-γ in the brain and spinal cord rapidly inhibits the spinal transmission of noxious inflammatory signals and local edema. These results suggest that PPAR-γ plays an important role in pain modulation in the central nervous system (Morgenweck et al, 2010) as well as in peripheral tissues and in peripheral endings of somatic afferents (Napimoga et al, 2008a;Pena-dos-Santos et al, 2009).…”

“…PPAR-γ agonists represent a promising therapeutic alternative for inflammatory diseases (Chima et al, 2008;Cuzzocrea et al, 2003;Kaplan et al, 2005;Napimoga et al, 2008aNapimoga et al, , 2008bPena-dos-Santos et al, 2009;Shan et al, 2004) and, in particular, they are extremely neuroprotective (Collino et al, 2006;Hyong et al, 2008;McTigue et al, 2007;Park et al, 2007;Pereira et al, 2006;Sundararajan et al, 2005;Tureyen et al, 2007;Zhao et al, 2005Zhao et al, , 2006. PPAR-γ was observed to be more expressive in ischemic neurons in rats with transient cerebral ischemia, suggesting that neuronal injury might alter PPAR-γ signaling (Victor et al, 2006).…”

“…Synthetic PPAR-γ agonists of the thiazolidinedione class act as insulin sensitizers and have become important in the treatment of type 2 diabetes (Lehrke and Lazar, 2005). PPAR ligands represent a promising therapeutic strategy for other diseases such as arthritis, sepsis, peritonitis, and colitis (Chima et al, 2008;Cuzzocrea et al, 2003;Kaplan et al, 2005;Napimoga et al, 2008aNapimoga et al, , 2008bShan et al, 2004), especially when it involves inflammatory pain (Pena-dos-Santos et al, 2009). Otherwise, PPAR-γ agonists are neuroprotective in animal models of acute central nervous system injury including focal ischemia, spinal cord injury and surgical trauma (Hyong et al, 2008;McTigue et al, 2007;Park et al, 2007;Pereira et al, 2006;Sundararajan et al, 2005;Tureyen et al, 2007;Zhao et al, 2005Zhao et al, , 2006.…”

Exogenous Administration of 15d-PGJ2–Loaded Nanocapsules Inhibits Bone Resorption in a Mouse Periodontitis Model

“…Recently, our and other research groups have demonstrated the anti-inflammatory activity of exogenously administered 15d-PGJ 2 (12)(13)(14)(15)(16)(17)(18). However, it has been estimated that .50% of the 15d-PGJ 2 added exogenously to a biological system binds to albumin (11).…”