Regulation of Inflammatory Pain by Inhibition of Fatty Acid Amide Hydrolase

Naidu, Pattipati S.; Kinsey, Steven G.; Guo, Tai L.; Cravatt, Benjamin F.; Lichtman, Aron H.

doi:10.1124/jpet.109.164806

Cited by 97 publications

(93 citation statements)

References 37 publications

(51 reference statements)

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“…Fatty acid amide hydrolase inhibitors, such as URB597 and OL135, are shown to be effective at reducing sensitivity to pain in acute and chronic experimental pain models (41,42). However, in a recent clinical trial, PF-04457845, an irreversible FAAH inhibitor, failed to induce effective analgesia in patients with knee osteoarthritis (43).…”

Section: Modulation Of the Endocannabinoid Systemmentioning

confidence: 99%

“…Thus, augmenting endocannabinoid levels in these structures will only effect CB receptors in these areas and possibly reduce central side effects. Inhibition of the degradative enzymes FAAH and MAGL, and inhibition of endocannabinoid cellular uptake are the pharmacological strategies used to modulate the endocannabinoid system and elevate endocannabinoid levels locally (3,5,22,38,40).Fatty acid amide hydrolase inhibitors, such as URB597 and OL135, are shown to be effective at reducing sensitivity to pain in acute and chronic experimental pain models (41,42). However, in a recent clinical trial, PF-04457845, an irreversible FAAH inhibitor, failed to induce effective analgesia in patients with knee osteoarthritis (43).…”

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confidence: 99%

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The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

Ulugöl¹

2014

Balkan Med J

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Cannabinoids are a group of chemical compounds that produce their effects via activating cannabinoid receptors; they include the phytocannabinoids (herbal cannabinoids/natural cannabinoids found in the cannabis plant), synthetic cannabinoids, and endogenous cannabinoids (endocannabinoids) (1, 2). Cannabis, also known as marijuana, has been used as both a recreational and medicinal drug for centuries. Pain management is the most important among the medicinal purposes, and has been drawing intense attention following the discovery of cannabinoid receptors and their endogenous ligands, endocannabinoids (3-5). ∆ 9 -tetrahydrocannabinol (THC) and cannabidiol, the critical components of the cannabis plant, and the synthetic cannabinoids and their analogues have been shown to exert strong analgesic action both in preclinical and clinical studies (6)(7)(8)(9). In this review, after a brief introduction to cannabinoid receptors, phytocannabinoids and synthetic cannabinoids, I provide an overview of what is currently known about the synthesis, release, degradation and biological actions of endocannabinoids, regarding their role in pain modulation, and describe the recent evidence of the promising results of augmentation of endogenous cannabinoid tonus for the treatment of pain. CANNABINOID RECEPTORS AND THE SITE OF ACTION OF CANNABINOIDSTo date, two subtypes of cannabinoid receptors, termed cannabinoid-1 (CB 1 ) and cannabinoid-2 (CB 2 ) receptors, have been cloned (10, 11). CB 1 receptors are most abundantly expressed in the central nervous system (CNS), most densely in motor and limbic regions, and in areas that are involved in pain transmission and modulation, such as periaqueductal grey (PAG), rostral ventromedial medulla (RVM), spinal cord dorsal horn, and in the periphery. CB 1 receptors are generally located pre-synaptically on axons and terminals of neurons and mediate the inhibition of neurotransmitter release by the inhibition of adenylate cyclase, blockade of voltage-dependent calcium channels, and/or by the activation of potassium channels and mitogen-activated protein kinase. CB 2 receptors, on the other hand, are found mainly, but not exclusively, outside the CNS, predominantly in peripheral tissues with immune functions, and most densely in the spleen. Similar to CB 1 receptors, CB 2 receptors are also G-protein coupled, inhibits adenylate cyclase and produce cellular inhibition, but neither blockade of calcium channels Although cannabis has been used for pain management for millennia, very few approved cannabinoids are indicated for the treatment of pain and other medical symptoms. Cannabinoid therapy re-gained attention only after the discovery of endocannabinoids and fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the enzymes playing a role in endocannabinoid metabolism. Nowadays, research has focused on the inhibition of these degradative enzymes and the elevation of endocannabinoid tonus locally; special emphasis is given on multi-target analgesia compounds, where one of the targe...

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Section: Modulation Of the Endocannabinoid Systemmentioning

confidence: 99%

mentioning

confidence: 99%

The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

Ulugöl¹

2014

Balkan Med J

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“…These discoveries thus lend further support to the hypothesis that multiple pathways exist for the biosynthesis of both NAEs and NATs in vivo. 4 -N -palmitoylethanolamine, and pentadecanoic acid (PDA) were purchased from Cayman Chemicals. C15:0-NAT and PF-3845 were synthesized as described previously ( 17,19 ).…”

Section: Measurement Of Tissue Lipidsmentioning

confidence: 99%

“…Anandamide acts as an endogenous ligand for the CB1 and CB2 receptors (3)(4)(5)(6), which are two G-protein-coupled recep-Gemini reverse-phase C18 column (5 µm, 4.6 mm × 50 mm; Phenomonex) together with a precolumn (C18, 3.5 µm, 2 mm × 20 mm). Mobile phase A was composed of 95:5 v/v H 2 O-MeOH, and mobile phase B was composed of 65:35:5 v/v/v i -PrOH-MeOH-H 2 O.…”

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confidence: 99%

An anatomical and temporal portrait of physiological substrates for fatty acid amide hydrolase

Long

LaCava

Jin

et al. 2011

Journal of Lipid Research

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tors that also respond to ⌬ 9 -tetrahydrocannabinol (THC), the psychoactive component of marijuana ( 7 ). The genetic or pharmacological inactivation of FAAH results in substantial increases in brain concentrations of anandamide and other N -acyl ethanolamine (NAE) lipids and produces several CB1-dependent neurobehavioral effects in rodents, including anxiolysis ( 8, 9 ), anti-depression ( 10 ), and anti-nociception ( 6,11,12 ). Interestingly, these effects are not accompanied by the cognitive and motor dysfunctions associated with direct CB1 agonists such as THC. Taken together, these fi ndings indicate that FAAH is a key regulator of endocannabinoid activity in vivo and suggest further that the enzyme might represent a therapeutic target for the treatment of pain and other nervous system disorders ( 13,14 ).FAAH-disrupted mice have also shown some phenotypes that are not reversed by the administration of CB1 or CB2 antagonists ( 12,15,16 ), suggesting that anandamide and/ or other FAAH substrates possess bioactivities that extend beyond the endocannabinoid system. To more broadly explore the physiological substrate pool regulated by FAAH, our laboratory has analyzed FAAH( Ϫ / Ϫ ) mice using a metabolomics method based on untargeted LC-MS ( 17 ). This approach confi rmed known elevations in anandamide and other NAEs in brains and livers of FAAH( Ϫ / Ϫ ) mice and also uncovered a novel class of natural products regulated by FAAH, the N -acyl taurines (NATs). Subsequent in vitro studies showed that FAAH can hydrolyze NATs and that NATs are agonists of the transient receptor potential family of ion channels at concentrations approximately equal to or lower than those found in certain tissues from FAAH( Ϫ / Ϫ ) mice ( 17, 18 ). Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase that degrades a number of bioactive lipid amides, including the endocannabinoid anandamide ( N -arachidonoyl ethanolamine) ( 1, 2 ). Anandamide acts as an endogenous ligand for the CB1 and CB2 receptors ( 3-6 ), which are two G-protein-coupled recep- Abstract Fatty acid amide hydrolase (FAAH) regulates amidated lipid transmitters, including the endocannabinoid anandamide and its N -acyl ethanolamine (NAE) congeners and transient receptor potential channel agonists N -acyl taurines (NATs). Using both the FAAH inhibitor PF-3845 and FAAH( ؊ /؊

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“…Several laboratories have reported inhibitory effects on inflammation and associated diseases and pathologic phenomena by elevating endogenous AEA levels through different approaches, including fatty acid amide hydrolase gene KO (Naidu et al, 2010;Kinsey et al, 2011;Wang et al, 2015), fatty acid amide hydrolase inhibitors (Kinsey et al, 2011;Schuelert et al, 2011;Booker et al, 2012;Caprioli et al, 2012;Kerr et al, 2012;Murphy et al, 2012;Sasso et al, 2012;Krustev et al, 2014;Sałaga et al, 2014;Tchantchou et al, 2014), and AEA reuptake inhibitors (Mestre et al, 2005;D'Argenio et al, 2006). Further studies are needed to address whether such approaches are also protective in glomerular injury associated with hHcys.…”

Section: Discussionmentioning

confidence: 99%

Protective Action of Anandamide and Its COX-2 Metabolite against L-Homocysteine-Induced NLRP3 Inflammasome Activation and Injury in Podocytes

Xia

Abais

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Recent studies have demonstrated that L-homocysteine (Hcys)-induced podocyte injury leading to glomerular damage or sclerosis is attributable to the activation of the nucleotidebinding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome. Given the demonstrated antiinflammatory effects of endocannabinoids, the present study was designed to test whether anandamide (AEA) or its metabolites diminish NLRP3 inflammasome activation and prevent podocyte injury and associated glomerular damage during hyperhomocysteinemia (hHcys). AEA (100 mM) inhibited Hcysinduced NLRP3 inflammasome activation in cultured podocytes, as indicated by elevated caspase-1 activity and interleukin-1b levels, and attenuated podocyte dysfunction, as shown by reduced vascular endothelial growth factor production. These effects of AEA were inhibited by the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CEL). In mice in vivo, AEA treatment attenuated glomerular NLRP3 inflammasome activation induced by hHcys accompanying a folate-free diet, on the basis of inhibition of hHcys-induced colocalization of NLRP3 molecules and increased interleukin-1b levels in glomeruli. Correspondingly, AEA prevented hHcys-induced proteinuria, albuminuria, and glomerular damage observed microscopically. Hcys-and AEA-induced effects were absent in NLRP3-knockout mice. These beneficial effects of AEA against hHcys-induced NLRP3 inflammasome activation and glomerular injury were not observed in mice cotreated with CEL. We further demonstrated that prostaglandin E2-ethanolamide (PGE2-EA), a COX-2 product of AEA, at 10 mM had a similar inhibitory effect to that of 100 mM AEA on Hcys-induced NLRP3 inflammasome formation and activation in cultured podocytes. From these results, we conclude that AEA has anti-inflammatory properties, protecting podocytes from Hcys-induced injury by inhibition of NLRP3 inflammasome activation through its COX-2 metabolite, PGE2-EA.

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Regulation of Inflammatory Pain by Inhibition of Fatty Acid Amide Hydrolase

Cited by 97 publications

References 37 publications

The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

An anatomical and temporal portrait of physiological substrates for fatty acid amide hydrolase

Protective Action of Anandamide and Its COX-2 Metabolite against L-Homocysteine-Induced NLRP3 Inflammasome Activation and Injury in Podocytes

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