Inhibition of Anandamide Hydrolysis by the Enantiomers of Ibuprofen, Ketorolac, and Flurbiprofen

Fowler, Christopher J.; Janson, Ulrika; Johnson, Randolph M.; Wahlström, Göran; Stenström, Anders; Norström, Åke; Tiger, Gunnar

doi:10.1006/abbi.1998.1025

Cited by 68 publications

(50 citation statements)

References 22 publications

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“…Indeed, the enzymatic hydrolysis of anandamide by FAAH is blocked by ibuprofen, ketorolac and flurbiprofen (Fowler et al, 1997(Fowler et al, , 1999) so that anandamide is not degraded, and thus, present locally in greater amounts to decrease pain behaviour. We have shown in a previous study that the combination of anandamide with ibuprofen produced synergistic antinociceptive effects but the mechanism of this interaction, although mediated in part by cannabinoid CB 1 and CB 2 receptors, was not clear (Guindon et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…However, other mechanisms have been proposed, such as interactions with endocannabinoids (Fowler et al, 1997). Indeed, FAAH activity, responsible for the degradation of anandamide, is inhibited by NSAIDs such as ibuprofen, ketorolac and flurbiprofen (Fowler et al, 1997(Fowler et al, , 1999. However, very little information is available in the literature on the antinociceptive effects of the combination of a cannabinoid with an NSAID.…”

Section: Introductionmentioning

confidence: 99%

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Synergistic antinociceptive effects of anandamide, an endocannabinoid, and nonsteroidal anti-inflammatory drugs in peripheral tissue: A role for endogenous fatty-acid ethanolamides?

Guindon

LoVerme

Léan

et al. 2006

European Journal of Pharmacology

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Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit fatty-acid amide hydrolase (FAAH), the enzyme responsible for the metabolism of anandamide, an endocannabinoid. It has been suggested that the mechanisms of action of NSAIDs could be due to inhibition of cyclooxygenase (COX) and also to an increase in endocannabinoid concentrations. In a previous study we have demonstrated that the local analgesic interaction between anandamide and ibuprofen (a non-specific COX inhibitor) was synergistic for the acute and inflammatory phases of the formalin test. To test this hypothesis further, we repeated similar experiments with rofecoxib (a selective COX-2 inhibitor) and also measured the local concentrations of anandamide, and of two fatty-acid amides, oleoylethanolamide and palmitoylethanolamide. We established the ED 50 for anandamide (34.52 pmol ± 17.26) and rofecoxib (381.72 pmol ± 190.86) and showed that the analgesic effect of the combination was synergistic. We also found that paw tissue levels of anandamide, oleoylethanolamide and palmitoylethanolamide were significantly higher when anandamide was combined with NSAIDs and that this effect was greater with rofecoxib. In conclusion, local injection of anandamide or rofecoxib was antinociceptive in a test of acute and inflammatory pain and the combination of anandamide with rofecoxib was synergistic. Finally, locally injected anandamide with either NSAID (ibuprofen or rofecoxib) generates higher amount of fatty-acid ethanolamides. The exact comprehension of the mechanisms involved needs further investigation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synergistic antinociceptive effects of anandamide, an endocannabinoid, and nonsteroidal anti-inflammatory drugs in peripheral tissue: A role for endogenous fatty-acid ethanolamides?

Guindon

LoVerme

Léan

et al. 2006

European Journal of Pharmacology

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“…Bishay et al (2010) found that systemically administered (R)-flurbiprofen alleviated mechanical hyperalgesia, cold allodynia and cold hyperalgesia in the spared nerve injury model of neuropathic pain accompanied by a normalisation of AEA levels in the dorsal root ganglia, dorsal horn and forebrain. (R)-flurbiprofen inhibits FAAH (Fowler et al 1999), but a key mechanism of action is its ability to block the oxygenation of eCBs at lower concentrations than are required for inhibition of arachidonic acid (Duggan et al 2011). This is also the case for an analogue of indomethacin, LM-4131, which increases brain AEA and to a lesser extent 2-AG concentrations.…”

Section: Oxygenating Enzymes (Cox-2)mentioning

confidence: 91%

The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

Fowler

2015

Handbook of Experimental Pharmacology

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The endocannabinoids anandamide and 2-arachidonoylglycerol are metabolised by both hydrolytic enzymes (primarily fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL)) and oxygenating enzymes (e.g. cyclooxygenase-2, COX-2). In the present article, the in vivo data for compounds inhibiting endocannabinoid metabolism have been reviewed, focussing on inflammation and pain. Potential reasons for the failure of an FAAH inhibitor in a clinical trial in patients with osteoarthritic pain are discussed. It is concluded that there is a continued potential for compounds inhibiting endocannabinoid metabolism in terms of drug development, but that it is wise not to be unrealistic in terms of expectations of success.

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“…La démonstration la plus pertinente actuellement, même si elle n'est pas, de notre point de vue, absolue, est celle de l'inhibition des effets antalgiques des AINS, administrés par voie intrathécale, par des antagonistes des récepteurs CB1, eux-mêmes injectés par voie centrale [2,21,32,68]. Il a, enfin, été montré que l'ibuprofène, le kétorolac et le flurbiprofène étaient capables d'inhiber la FAAH, enzyme qui permet la dégradation de l'anandamide [26,27,33].…”

Section: Un Mécanisme Faisant Intervenir Les Endocannabinoïdesunclassified

Composante centrale de l’effet analgésique des AINS

Kresec¹,

Richard²,

Busserolles³

et al. 2007

Douleur analg.

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Les anti-inflammatoires non stéroïdiens (AINS) sont classiquement considérés comme des antalgiques périphériques réduisant la douleur inflammatoire en inhibant les cyclo-oxygénases, impliquées dans la synthèse des prostaglandines. Cependant, des preuves pharmacocinétiques et pharmacodynamiques ont été accumulées en faveur d'un effet central des AINS pour lequel différentes hypothèses mécanistiques ont pu être évoquées, en particulier une implication des cyclo-oxygénases présentes dans le système nerveux central. Cette revue a pour objectifs : 1) de rappeler les arguments qui plaident pour un effet central des AINS ; 2) d'évoquer les mécanismes de cette action centrale (une place importante sera faite à la cascade phospholipases-cyclo-oxygénases-prostaglandines, mécanisme vraisemblablement prioritaire) ; 3) d'éva-luer au travers de données de la littérature la part respective de la composante périphérique et de la composante centrale dans l'effet antalgique résultant. Les AINS sont capables de diffuser au travers de la barrière hématoencéphalique et d'exercer après administration centrale dans des modèles de douleur inflammatoire ou après administration systémique sur des modèles animaux ou humains de douleur non inflammatoire, un effet antalgique. Les éléments de la cascade évoquée plus haut sont présents dans la corne postérieure de la moelle épinière, une augmentation du fonctionnement de cette cascade a été observée en condition d'inflammation, les AINS sont capables de réduire cette augmentation. Quelques études permettent de considérer que la participation centrale à l'effet des AINS varie en fonction des molécules, qu'elle peut être impliquée dans l'effet précoce des AINS administrés par voie systémique ou dans l'effet de petites doses. Enfin, cet effet central réduirait particulièrement le phénomène d'hyperalgésie secondaire.Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are usually considered peripherally acting analgesics that inhibit the cyclooxygenases implicated in prostaglandin biosynthesis. However, different pharmacokinetic and pharmacodynamic evidences suggest the involvement of cyclooxygenases (COX) in the central nervous system as well as other possible mechanisms. The purpose of this review is to: 1) present arguments supporting centrally acting NSAIDs;

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Inhibition of Anandamide Hydrolysis by the Enantiomers of Ibuprofen, Ketorolac, and Flurbiprofen

Cited by 68 publications

References 22 publications

Synergistic antinociceptive effects of anandamide, an endocannabinoid, and nonsteroidal anti-inflammatory drugs in peripheral tissue: A role for endogenous fatty-acid ethanolamides?

Synergistic antinociceptive effects of anandamide, an endocannabinoid, and nonsteroidal anti-inflammatory drugs in peripheral tissue: A role for endogenous fatty-acid ethanolamides?

The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

Composante centrale de l’effet analgésique des AINS

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