Synergistic antinociception by the cannabinoid receptor agonist anandamide and the PPAR-α receptor agonist GW7647

Russo, Roberto; LoVerme, Jesse; Rana, Giovanna La; D’Agostino, Giuseppe; Sasso, Oscar; Calignano, Antonio; Piomelli, Daniele

doi:10.1016/j.ejphar.2007.03.007

Cited by 51 publications

(50 citation statements)

References 17 publications

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“…The actions of PEA also may be due the actions of its metabolites, particularly in the repeated dosing study, or downstream targets of this FAA. Recently, activation of the large conductance potassium channel (K CA 1.1, BK, slo) a downstream target of PPAR-α receptor agonists, which may be an important target for PEA, was found to reduce pain in the formalin model and to act synergistically with anandamide to reduce pain (Russo et al, 2007). The PPAR-α receptor agonist GW7647 and anandamide were found to produce synergistic antinociception in this same study.…”

Section: Discussionmentioning

confidence: 49%

Evaluation of fatty acid amides in the carrageenan-induced paw edema model

et al. 2008

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While it has long been recognized that Δ 9 -tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, and other cannabinoid receptor agonists possess anti-inflammatory properties, their well known CNS effects have dampened enthusiasm for therapeutic development. On the other hand, genetic deletion of fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of fatty acid amides, including endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA), N-palmitoyl ethanolamine (PEA), N-oleoyl ethanolamine (OEA), and oleamide, also elicits anti-edema, but does not produce any apparent cannabinoid effects. The purpose of the present study was to investigate whether exogenous administration of FAAs would augment the anti-inflammatory phenotype of FAAH (-/-) mice in the carrageenan model. Thus, we evaluated the effects of the FAAs AEA, PEA, OEA, and oleamide in wild-type and FAAH (-/-) mice. For comparison, we evaluated the anti-edema effects of THC, dexamethasone (DEX), a synthetic glucocorticoid, diclofenac (DIC), a nonselective cyclooxygenase (COX) inhibitor, in both genotypes. A final study determined if tolerance to the anti-edema effects of PEA occurs after repeated dosing. PEA, THC, DEX, DIC elicited significant decreases in carrageenan-induced paw edema in wild type mice. In contrast OEA produced a less reliable anti-edema effect than these other drugs, and AEA and oleamide failed to produce any significant decreases in paw edema. Moreover, none of the agents evaluated augmented the anti-edema phenotype of FAAH (-/-) mice, suggesting that maximal antiedema effects had already been established. PEA was the most effective FAA in preventing paw edema and its effects did not undergo tolerance. While the present findings do not support a role for AEA in preventing carrageenan-induced edema, PEA administration and FAAH blockade elicited anti-edema effects of an equivalent magnitude as produced by THC, DEX, and DIC in this assay.

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Section: Discussionmentioning

confidence: 49%

Evaluation of fatty acid amides in the carrageenan-induced paw edema model

et al. 2008

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“…Indeed, it has been demonstrated that cannabinoid receptor agonists present effect via activation of the PPAR-␥ receptor. Although we did not investigate the participation of endogenous cannabinoids in the antinociceptive action of 15d-PGJ 2 , there is evidence that PPAR-␣ synergizes with cannabinoids to produce analgesia (Russo et al, 2007). Therefore, further studies are necessary to elucidate the contribution of endocannabinoids to the antinociceptive effect of 15d-PGJ 2 .…”

Section: Discussionmentioning

confidence: 99%

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

Napimoga

Souza²,

Cunha³

et al. 2007

J Pharmacol Exp Ther

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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.

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“…For example, even though systemic administration of a selective CB 1 receptor agonist has been shown to increase nicotine selfadministration in rats (Gamaleddin et al, 2012), indirectly enhancing endocannabinoid signaling by FAAH inhibition dampens nicotine-induced firing of dopamine cells in the nucleus accumbens through both PPAR-α and CB 1 receptors (Luchicchi et al, 2010;Melis et al, 2010). Moreover, it has been shown that potentiation of FAE signaling at PPAR-α by FAAH inhibition can have various consequences, including functional interactions with signaling at CB 1 receptors (Russo et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse

Justinová

Panlilio

Moreno-Sanz

et al. 2015

Neuropsychopharmacol

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Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first-and second-generation O-arylcarbamatebased FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-ylcyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors; (2) shifted nicotine self-administration dose-response functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB 1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell-consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement.

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Synergistic antinociception by the cannabinoid receptor agonist anandamide and the PPAR-α receptor agonist GW7647

Cited by 51 publications

References 17 publications

Evaluation of fatty acid amides in the carrageenan-induced paw edema model

Evaluation of fatty acid amides in the carrageenan-induced paw edema model

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

Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse

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Synergistic antinociception by the cannabinoid receptor agonist anandamide and the PPAR-α receptor agonist GW7647

Cited by 51 publications

References 17 publications

Evaluation of fatty acid amides in the carrageenan-induced paw edema model

Evaluation of fatty acid amides in the carrageenan-induced paw edema model

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

Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse

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