Arachidonoylserotonin and Other Novel Inhibitors of Fatty Acid Amide Hydrolase

Bisogno, Tiziana; Melck, Dominique; Petrocellis, Luciano De; Bobrov, M. Yu.; Gretskaya, N. M.; Безуглов, В. В.; Sitachitta, Namthip; Gerwick, William H.; Marzo, Vincenzo Di

doi:10.1006/bbrc.1998.8874

Cited by 177 publications

(139 citation statements)

References 35 publications

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“…The present study therefore investigates the impact of [3-(3-carbamoylphenyl)phenyl] N -cyclohexylcarbamate (URB597), an irreversible carbamate-based FAAH inhibitor (47)(48)(49), and N -arachidonoyl serotonin (AA-5HT), an endogenous molecule with FAAH inhibitory activity ( 50 ), as well as of the FAAH substrates, AEA, 2-AG, OEA, and PEA, on the migration of human MSCs and the mechanism underlying a potential response. Here we present evidence for a promigratory action of these substances involving initial phosphorylation of p42/44 MAPK and subsequent activation of PPAR ␣ .…”

Section: Migration Assaymentioning

confidence: 99%

Inhibition of FAAH confers increased stem cell migration via PPARα

Wollank

Ramer

Ivanov

et al. 2015

Journal of Lipid Research

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review see ( 1 )]. As a consequence, components of this system, as well as pharmacological strategies to block endocannabinoid degradation, have been elucidated in past years [for review see ( 2 )].An integral component of the endocannabinoid system is the enzyme, fatty acid amide hydrolase (FAAH), a serine hydrolase fi rst identifi ed as the principal catabolic enzyme of the endocannabinoid, anandamide [ N -arachidonoylethanolamine (AEA)] ( 3 ). The second major endocannnabinoid, 2-arachidonoylglycerol (2-AG), can be hydrolyzed by multiple enzymes, including FAAH and monoacylglycerol lipase (MAGL), with about 85% of brain 2-AG hydrolase activity ascribed to MAGL ( 4 ). Likewise, FAAH is the catabolic enzyme for the endocannabinoid-like substances, Noleoylethanolamine (OEA) and N -palmitoylethanolamine (PEA) ( 5 ). In contrast to AEA and 2-AG, both endocannabinoid-like substances do not bind to the cannabinoid receptors, CB 1 and CB 2 , but share an activation of the nonselective cation channel transient receptor potential vanilloid 1 (TRPV1) ( 6-9 ) and the transcription factor PPAR ␣ ( 10-16 ) with endocannabinoids. In line with the latter notion, various biological effects of FAAH inhibitors have been associated with activation of PPAR ␣ ( 17-21 ).Several components of the endocannabinoid system, including CB 1 , CB 2 , TRPV1, and cannabinoid receptor ligands, have been reported as effectors of tissue healing

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Section: Migration Assaymentioning

confidence: 99%

Inhibition of FAAH confers increased stem cell migration via PPARα

Wollank

Ramer

Ivanov

et al. 2015

Journal of Lipid Research

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“…URB597 68 is a well-characterized irreversible inhibitor of FAAH (IC 50 = 4.6 nM) that lacks signifi cant affi nity for CB 1 and CB 2 receptors and does not affect MGL, acetyl-cholinesterase, butyryl-cholinesterase, or the anandamide membrane transporter at concentrations up to 300 μM. Arachidonoylserotonin 69 is a novel FAAH inhibitor that inhibits anandamide hydrolysis (IC 50 = 5.6 μM), lacks affi nity for CB 1 , and does not signifi cantly affect the cellular uptake of anandamide at 25 μM. MGL can be inhibited by a variety of nonselective serine hydrolase inhibitors (eg, methyl arachidonoyl fl uorophosphonate).…”

Section: Cannabinoid Receptor Pharmacology and Exogenous Cannabinoid mentioning

confidence: 99%

Endocannabinoid mechanisms of pain modulation

Hohmann

Suplita

2006

AAPS J

187

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Cannabinoids are antinociceptive in animal models of acute, tissue injury -, and nerve injury -induced nociception. This review examines the biology of endogenous cannabinoids (endocannabinoids) and behavioral, neurophysiological, and neuroanatomical evidence supporting the notion that cannabinoids play a role in pain modulation. Behavioral pharmacological approaches, in conjunction with the identifi cation and quantifi cation of endocannabinoids through the use of liquid and gas chromatography mass spectrometry, have provided insight into the functional roles of en docannabinoids in pain modulation. Here we examine the distribution of cannabinoid receptors and endocannabinoid-hydrolyzing enzymes within pain modulatory circuits to gether with behavioral, neurochemical, and neurophysiological studies that suggest a role for endocannabinoid signaling in pain modulation. This review will provide a comprehensive evaluation of the roles of the endocannabinoids 2-arachidonoylglycerol and anandamide in stress-induced analgesia. These fi ndings provide a functional framework with which to understand the roles of endocannabinoids in nociceptive processing at the supraspinal level.K EYWORDS: 2-arachidonoylglycerol , anandamide , CB1 , fatty acid amide hydrolase , monoacylglycerol lipase , periaqueductal gray , rostral ventromedial medulla

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“…Moreover, we used selective inhibitors of MGL (URB602; Hohmann et al, 2005) and FAAH (URB597; Kathuria et al, 2003) to further elucidate the roles of these endocannabinoids in SIA. We additionally evaluated effects of intrathecal administration of arachidonoylserotonin (AA-5-HT; Bisogno et al, 1998), a FAAH inhibitor that is inactive at phospholipase A 2 and CB 1 receptors, on SIA. We hypothesized that intrathecal administration of these inhibitors would potentiate nonopioid SIA via a CB 1 mechanism.…”

Section: Introductionmentioning

confidence: 99%

Endocannabinoids at the spinal level regulate, but do not mediate, nonopioid stress-induced analgesia

et al. 2006

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Recent work in our laboratories has demonstrated that an opioid-independent form of stress-induced analgesia (SIA) is mediated by endogenous cannabinoids [Hohmann et al., 2005. Nature 435, 1108. Non-opioid SIA, induced by a 3-min continuous foot shock, is characterized by the mobilization of two endocannabinoid lipidsd2-arachidonoylglycerol (2-AG) and anandamidedin the midbrain periaqueductal gray (PAG). The present studies were conducted to examine the contributions of spinal endocannabinoids to nonopioid SIA. Time-dependent increases in levels of 2-AG, but not anandamide, were observed in lumbar spinal cord extracts derived from shocked relative to non-shocked rats. Notably, 2-AG accumulation was of smaller magnitude than that observed previously in the dorsal midbrain following foot shock. 2-AG is preferentially degraded by monoacylglycerol lipase (MGL), whereas anandamide is hydrolyzed primarily by fatty-acid amide hydrolase (FAAH). This metabolic segregation enabled us to manipulate endocannabinoid tone at the spinal level to further evaluate the roles of 2-AG and anandamide in nonopioid SIA. Intrathecal administration of the competitive CB 1 antagonist SR141716A (rimonabant) failed to suppress nonopioid SIA, suggesting that supraspinal rather than spinal CB 1 receptor activation plays a pivotal role in endocannabinoid-mediated SIA. By contrast, spinal inhibition of MGL using URB602, which selectively inhibits 2-AG hydrolysis in the PAG, enhanced SIA through a CB 1 -selective mechanism. Spinal inhibition of FAAH, with either URB597 or arachidonoyl serotonin (AA-5-HT), also enhanced SIA through a CB 1 -mediated mechanism, presumably by increasing accumulation of tonically released anandamide. Our results suggest that endocannabinoids in the spinal cord regulate, but do not mediate, nonopioid SIA.

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Arachidonoylserotonin and Other Novel Inhibitors of Fatty Acid Amide Hydrolase

Cited by 177 publications

References 35 publications

Inhibition of FAAH confers increased stem cell migration via PPARα

Inhibition of FAAH confers increased stem cell migration via PPARα

Endocannabinoid mechanisms of pain modulation

Endocannabinoids at the spinal level regulate, but do not mediate, nonopioid stress-induced analgesia

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