Inhibition of fatty acid amide hydrolase and cyclooxygenase-2 increases levels of endocannabinoid related molecules and produces analgesia via peroxisome proliferator-activated receptor-alpha in a model of inflammatory pain

Jhaveri, Maulik D.; Richardson, Denise; Robinson, Ian; Garle, Michael J.; Patel, Annie; Sun, Yan; Sagar, Devi Rani; Bennett, Andrew J.; Alexander, Stephen P.H.; Kendall, David A.; Barrett, David A.; Chapman, Victoria

doi:10.1016/j.neuropharm.2008.04.018

Cited by 112 publications

(100 citation statements)

References 55 publications

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“…Alternatively, or in addition, PEA may exert effects directly through its actions at non-CB 1 receptor targets including peroxisome-prolierator-activated receptors (PPARα; [37,47]) and GPR55 [30]. It is worth noting that while rimonabant blocked the URB597-induced enhancement of FCA, it did not by itself have any effect on FCA.…”

Section: Discussionmentioning

confidence: 99%

A role for the ventral hippocampal endocannabinoid system in fear-conditioned analgesia and fear responding in the presence of nociceptive tone in rats

Ford

Kieran

Dolan

et al. 2011

Pain

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Section: Discussionmentioning

confidence: 99%

A role for the ventral hippocampal endocannabinoid system in fear-conditioned analgesia and fear responding in the presence of nociceptive tone in rats

Ford

Kieran

Dolan

et al. 2011

Pain

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“…The demonstration that, at least in cells, 15-LOX is capable of metabolizing 2-AG to 15-HETE-G (see references in Vandevoorde & Lambert [112]), which is a ligand for the antiinflammatory nuclear receptor PPARa [28], suggests that changes in LOX expression and metabolism of endocannabinoids via this pathway may also influence nociceptive processing. Indeed, we and others have shown that PPARa ligands can have marked inhibitory effects on inflammatory pain responses (see references in [113][114][115][116]). …”

Section: Effects Of Novel Biological Metabolites Of 2-ag and Anandamidementioning

confidence: 91%

Dynamic changes to the endocannabinoid system in models of chronic pain

Sagar

Burston

Woodhams

et al. 2012

Phil. Trans. R. Soc. B

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The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling.

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“…Conversely, systemic administration of the FAAH inhibitor URB597 reduces carrageenan-induced paw edema through a CB 2 receptor mechanism of action (33). Intraplantar administration of URB597 does not reduce edema but reduces differential weight bearing in inflamed paws (34) as well as the expansion of the nociceptor field size (35).…”

Section: Carrageenan Inflammation Modelmentioning

confidence: 99%

Targeting Fatty Acid Amide Hydrolase (FAAH) to Treat Pain and Inflammation

Schlosburg

Kinsey

Lichtman

2009

AAPS J

142

112

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Abstract. The endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA) produces most of its pharmacological effects by binding and activating CB 1 and CB 2 cannabinoid receptors within the CNS and periphery. However, the actions of AEA are short lived because of its rapid catabolism by fatty acid amide hydrolase (FAAH). Indeed, FAAH knockout mice as well as animals treated with FAAH inhibitors are severely impaired in their ability to hydrolyze AEA as well as a variety of noncannabinoid lipid signaling molecules and consequently possess greatly elevated levels of these endogenous ligands. In this mini review, we describe recent research that has investigated the functional consequences of inhibiting this enzyme in a wide range of animal models of inflammatory and neuropathic pain states. FAAH-compromised animals reliably display antinociceptive and antiinflammatory phenotypes with a similar efficacy as direct-acting cannabinoid receptor agonists, such as Δ 9 -tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis sativa. Importantly, FAAH blockade does not elicit any apparent psychomimetic effects associated with THC or produce reinforcing effects that are predictive of human drug abuse. The beneficial effects caused by FAAH blockade in these models are predominantly mediated through the activation of CB 1 and/or CB 2 receptors, though noncannabinoid mechanisms of actions can also play contributory or even primary roles. Collectively, the current body of scientific literature suggests that activating the endogenous cannabinoid system by targeting FAAH is a promising strategy to treat pain and inflammation but lacks untoward side effects typically associated with Cannabis sativa.KEY WORDS: anandamide; CB 1 cannabinoid receptor; CB 2 cannabinoid receptor; endogenous cannabinoid; fatty acid amide hydrolase (FAAH); inflammatory pain; neuropathic pain.

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Inhibition of fatty acid amide hydrolase and cyclooxygenase-2 increases levels of endocannabinoid related molecules and produces analgesia via peroxisome proliferator-activated receptor-alpha in a model of inflammatory pain

Cited by 112 publications

References 55 publications

A role for the ventral hippocampal endocannabinoid system in fear-conditioned analgesia and fear responding in the presence of nociceptive tone in rats

A role for the ventral hippocampal endocannabinoid system in fear-conditioned analgesia and fear responding in the presence of nociceptive tone in rats

Dynamic changes to the endocannabinoid system in models of chronic pain

Targeting Fatty Acid Amide Hydrolase (FAAH) to Treat Pain and Inflammation

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