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Daniele Piomelli - One of the best experts on this subject based on the ideXlab platform.
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Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat
Psychopharmacology, 2008Co-Authors: Andrea Cippitelli, Andrea Duranti, Daniele Piomelli, Andrea Tontini, Nazzareno Cannella, Simone Braconi, Ainhoa Bilbao, Fernando Rodríguez Defonseca, Roberto CiccocioppoAbstract:Rationale A major clinical concern with the use of cannabinoid receptor 1 (CB1) direct agonists is that these compounds increase alcohol drinking and drug abuse-related behaviours. As an alternative approach, CB1-receptor-mediated activity can be facilitated by increasing anandamide levels with the use of hydrolase fatty acid amide hydrolase (FAAH) inhibitors. Objective Using the selective FAAH inhibitor URB597, we investigated whether activation of the endogenous cannabinoid tone increases alcohol abuse liability, as what happens with the CB1 receptor direct agonists. Materials and methods URB597 was tested on alcohol self-administration in Wistar rats and on homecage alcohol drinking in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. In Wistar rats, URB597 effects on alcohol-induced anxiety and on stress-, yohimbine- and cue-induced reinstatement of alcohol seeking were also evaluated. For comparison, the effect of the CB1 receptor antagonist rimonabant on ethanol self-administration was also tested. Results Under our experimental condition, intraperitoneal (IP) administration of URB597 (0.0, 0.3 and 1.0 mg/kg) neither increased voluntary homecage alcohol drinking in msP rats nor facilitated fixed ratio 1 and progressive ratio alcohol self-administration in nonselected Wistars. In the reinstatement tests, the compound did not have effects on cue-, footshock stress- and yohimbine-induced relapse. Conversely, URB597 completely abolished the anxiogenic response measured during withdrawal after an acute IP administration of alcohol (3.0 g/kg). Rimonabant (0.0, 0.3, 1.0 and 3.0 mg/kg) significantly reduced ethanol self-administration. Conclusions Results demonstrate that activation of the endocannabinoid anandamide system by selective inhibition of FAAH does not increase alcohol abuse risks but does reduce anxiety associated to alcohol withdrawal. We thus can speculate that medication based on the use of endocannabinoid system modulators such as URB597 may offer important advantages compared to treatment with direct CB1 receptor activators.
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the endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase faah inhibition
Neuropharmacology, 2008Co-Authors: Maria Scherma, Julie Medalie, Walter Fratta, Subramanian K Vadivel, Alexandros Makriyannis, Daniele Piomelli, Eva Mikics, Jozsef Haller, Sevil Yasar, Gianluigi TandaAbstract:Abstract Converging evidence suggests that the endocannabinoid system is an important constituent of neuronal substrates involved in brain reward processes and emotional responses to stress. Here, we evaluated motivational effects of intravenously administered anandamide, an endogenous ligand for cannabinoid CB1-receptors, in Sprague–Dawley rats, using a place-conditioning procedure in which drugs abused by humans generally produce conditioned place preferences (reward). Anandamide (0.03–3 mg/kg intravenous) produced neither conditioned place preferences nor aversions. However, when rats were pre-treated with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (cyclohexyl carbamic acid 3′-carbamoyl-3-yl ester; 0.3 mg/kg intraperitoneal), which blocks anandamide's metabolic degradation, anandamide produced dose-related conditioned place aversions. In contrast, URB597 alone showed no motivational effects. Like URB597 plus anandamide, the synthetic CB1-receptor ligand WIN 55,212-2 (50–300 μg/kg, intravenous) produced dose-related conditioned place aversions. When anxiety-related effects of anandamide and URB597 were evaluated in a light/dark box, both a low anandamide dose (0.3 mg/kg) and URB597 (0.1 and 0.3 mg/kg) produced anxiolytic effects when given alone, but produced anxiogenic effects when combined. A higher dose of anandamide (3 mg/kg) produced anxiogenic effects and depressed locomotor activity when given alone and these effects were potentiated after URB597 treatment. Finally, anxiogenic effects of anandamide plus URB597 and development of place aversions with URB597 plus anandamide were prevented by the CB1-receptor antagonist AM251 (3 mg/kg intraperitoneal). Thus, additive interactions between the effects of anandamide on brain reward processes and on anxiety may account for its aversive effects when intravenously administered during FAAH inhibition with URB597.
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antidepressant like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress
Biological Psychiatry, 2007Co-Authors: Marco Bortolato, Andrea Duranti, Andrea Tontini, Giorgio Tarzia, Regina A Mangieri, Jin Fu, Oliver Arguello, Daniele PiomelliAbstract:BACKGROUND: The endocannabinoid anandamide may be involved in the regulation of emotional reactivity. In particular, it has been shown that pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of anandamide, elicits anxiolytic-like and antidepressant-like effects in rodents. METHODS: We investigated the impact of chronic treatment with the selective FAAH inhibitor, URB597 (also termed KDS-4103), on the outcomes of the chronic mild stress (CMS) in rats, a behavioral model with high isomorphism to human depression. RESULTS: Daily administration of URB597 (.3 mg kg(-1), intraperitoneal [IP]) for 5 weeks corrected the reduction in body weight gain and sucrose intake induced by CMS. The antidepressant imipramine (20 mg kg(-1), once daily, IP) produced a similar response, whereas lower doses of URB597 were either marginally effective (.1 mg kg(-1)) or ineffective (.03 mg kg(-1)). Treatment with URB597 (.3 mg kg(-1)) resulted in a profound inhibition of brain FAAH activity in both CMS-exposed and control rats. Furthermore, the drug regimen increased anandamide levels in midbrain, striatum, and thalamus. CONCLUSIONS: URB597 exerts antidepressant-like effects in a highly specific and predictive animal model of depression. These effects may depend on the ability of URB597 to enhance anandamide signaling in select regions of the brain.
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the fatty acid amide hydrolase inhibitor URB597 cyclohexylcarbamic acid 3 carbamoylbiphenyl 3 yl ester reduces neuropathic pain after oral administration in mice
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Roberto Russo, Andrea Duranti, Andrea Tontini, Giorgio Tarzia, Jesse Loverme, Giovanna La Rana, Timothy R Compton, Jeff A Parrott, Antonio Calignano, Daniele PiomelliAbstract:Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of bioactive fatty acid ethanolamides, such as the endogenous cannabinoid agonist anandamide. Genetic deletion of the faah gene in mice elevates brain anandamide levels and amplifies the antinociceptive effects of this compound. Likewise, pharmacological blockade of FAAH activity reduces nocifensive behavior in animal models of acute and inflammatory pain. In the present study, we investigated the effects of the selective FAAH inhibitor URB597 (KDS-4103, cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester) in the mouse chronic constriction injury (CCI) model of neuropathic pain. Oral administration of URB597 (1–50 mg/kg, once daily) for 4 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single i.p. administration of the cannabinoid CB 1 receptor antagonist rimonabant (1 mg/kg). The antihyperalgesic effects of URB597 were accompanied by a reduction in plasma extravasation induced by CCI, which was prevented by rimonabant (1 mg/kg i.p.) and attenuated by the CB 2 antagonist SR144528 (1 mg/kg i.p.). Oral dosing with URB597 achieved significant, albeit transient, drug levels in plasma, inhibited brain FAAH activity, and elevated spinal cord anandamide content. The results provide new evidence for a role of the endocannabinoid system in pain modulation and reinforce the proposed role of FAAH as a target for analgesic drug development.
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Effects of the FAAH inhibitor, URB597, and anandamide on lithium-induced taste reactivity responses: a measure of nausea in the rat
Psychopharmacology, 2007Co-Authors: Shelley K. Cross-mellor, Daniele Piomelli, Klaus-peter Ossenkopp, Linda A ParkerAbstract:Rationale The endogenous cannabinoid system plays a vital role in the control of nausea and emesis. Because of the rapid breakdown and hydrolysis of endocannabinoids, such as anandamide, the therapeutic effects may be enhanced by prolonging their duration of action. Objective The present experiment evaluated the potential of various doses of URB597, a fatty acid amide hydrolase (FAAH) inhibitor, alone and in combination with systemic administration of anandamide to modulate the establishment of lithium-induced conditioned taste reactivity responses in rats. Materials and methods In experiment 1, on the conditioning day, rats first received an injection of 0.3 mg/kg URB597, 0.15 mg/kg URB597, or vehicle and then received a second injection of anandamide (5 mg/kg) or vehicle, before a 3-min exposure of 0.1% saccharin by intraoral infusion. Immediately after the saccharin exposure, the rats were injected with lithium chloride. On each of three test days, rats received a 3-min intraoral infusion of saccharin solution, and the taste reactivity responses were videotaped and monitored. In experiment 2, the effects of pretreatment with the CB_1 antagonist, AM-251, on URB597 and anandamide-induced suppressed aversion was evaluated. Results Administration of URB597 alone and in combination with anandamide reduced active rejection reactions elicited by a LiCl-paired saccharin solution; both effects were reversed by pretreatment with AM-251, suggesting that they were CB_1 receptor mediated. Conclusions The results suggest that prolonging the action of anandamide by pretreatment with the FAAH inhibitor, URB597, suppresses lithium-induced nausea in the rat.
Andrea Duranti - One of the best experts on this subject based on the ideXlab platform.
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The fatty acid amide hydrolase inhibitor URB597 modulates serotonin-dependent emotional behaviour, and serotonin1A and serotonin2A/C activity in the hippocampus.
European Neuropsychopharmacology, 2016Co-Authors: Francis Rodriguez Bambico, Andrea Duranti, José N. Nobrega, Gabriella GobbiAbstract:The fatty acid amide hydrolase (FAAH) inhibitor URB597 increases anandamide, resulting in antidepressant/anxiolytic-like activity, likely via CB1 receptor-mediated modulation of serotonin (5-HT) and norepinephrine (NE) neurotransmission. However, the relative importance of the 5-HT and NE systems in these effects and on effects of URB597 on postsynaptic 5-HT receptors remain to be determined. Using behavioural and electrophysiological approaches, we assessed the effects of acute-single and repeated URB597 treatment on responses predicting antidepressant/anxiolytic activity, and on hippocampal 5-HT1A and 5-HT2A/C receptor sensitivity. Acute-single or serial URB597 treatment, compared to vehicle, reduced immobility in the forced swim test (FST), increased open arm visits in the elevated plus maze and shortened feeding latency in the novelty-suppressed feeding test (NSFT). Repeated URB597 treatment yielded more profound behavioural effects, which were associated with an increase in hippocampal brain-derived neurotrophic factor (BDNF). The 5-HT synthesis inhibitor para-chlorophenylalanine (pCPA), but not the NE neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) prevented URB597-mediated antidepressant/anxiolytic-like response in the FST and NSFT, while DSP4 did not further affect URB597-mediated increase in raphe 5-HT neuron firing. Repeated URB597 administration decreased hippocampal pyramidal firing in response to 5-HT2A/C and 5-HT1A stimulation with 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) and 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT), respectively, suggesting plastic adaptation of these receptors. The effects of acute-single and repeated URB597 administration on hippocampal cell firing in response to DOI or 8-OH-DPAT were similar in magnitude and intensity to the positive control citalopram. These data indicate that URB597 acts, either directly or indirectly, on the 5-HT system, increases hippocampal BDNF expression, and modifies 5-HT1A and 5-HT2A/C function.
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Inhibition of anandamide hydrolysis enhances noradrenergic and GABAergic transmission in the prefrontal cortex and basolateral amygdala of rats subjected to acute swim stress
Journal of Neuroscience Research, 2015Co-Authors: Gaurav Bedse, Andrea Duranti, Adele Romano, Carlo Cifani, Bianca Tempesta, Michele Angelo Lavecchia, Lorenzo Pace, Antonello Bellomo, Maria Vittoria Micioni Di Bonaventura, Tommaso CassanoAbstract:Limbic forebrain endocannabinoid (eCB) signaling is critically involved in stress integration by modulating neurotransmitters release. The purpose of this study was to examine, by brain microdialysis, the effects of fatty acid amide hydrolase (FAAH) inhibition on noradrenergic and γ-aminobutyric acid (GABA)-ergic neurotransmission in the prefrontal cortex (PFC) and basolateral amygdala (BLA) of rats subjected to a 20-min swim stress. Microdialysis started on stress- and drug-naive rats that were treated with the FAAH inhibitor URB597 (0.1 or 0.3 mg/kg) 30 min before undergoing the stress procedure. Dialysate samples were collected every 20 min from the beginning of the experiment. Concentrations of noradrenaline (NA) and GABA were determined by HPLC coupled to electrochemical and fluorescence detection, respectively. We found that neither URB597 treatment nor 20 min of swim stress exposure per se altered NA and GABA extracellular levels in PFC or BLA. Interestingly, rats treated with 0.1 mg/kg of URB597 followed by 20 min of stress showed significantly higher NA and GABA levels in PFC and BLA. These effects were absent in rats treated with 0.3 mg/kg URB597, indicating a dose-specific effect. Moreover, we found that the pretreatment with the CB1 receptor antagonist rimonabant blocked the URB597 effects on NA and GABA release in PFC and BLA of animals subjected to forced swimming. The present study might provide an important first step toward understanding the mechanisms through which URB597 modulates stress-induced neuroendocrine secretion and behavioral coping strategies.
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Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat
Psychopharmacology, 2008Co-Authors: Andrea Cippitelli, Andrea Duranti, Daniele Piomelli, Andrea Tontini, Nazzareno Cannella, Simone Braconi, Ainhoa Bilbao, Fernando Rodríguez Defonseca, Roberto CiccocioppoAbstract:Rationale A major clinical concern with the use of cannabinoid receptor 1 (CB1) direct agonists is that these compounds increase alcohol drinking and drug abuse-related behaviours. As an alternative approach, CB1-receptor-mediated activity can be facilitated by increasing anandamide levels with the use of hydrolase fatty acid amide hydrolase (FAAH) inhibitors. Objective Using the selective FAAH inhibitor URB597, we investigated whether activation of the endogenous cannabinoid tone increases alcohol abuse liability, as what happens with the CB1 receptor direct agonists. Materials and methods URB597 was tested on alcohol self-administration in Wistar rats and on homecage alcohol drinking in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. In Wistar rats, URB597 effects on alcohol-induced anxiety and on stress-, yohimbine- and cue-induced reinstatement of alcohol seeking were also evaluated. For comparison, the effect of the CB1 receptor antagonist rimonabant on ethanol self-administration was also tested. Results Under our experimental condition, intraperitoneal (IP) administration of URB597 (0.0, 0.3 and 1.0 mg/kg) neither increased voluntary homecage alcohol drinking in msP rats nor facilitated fixed ratio 1 and progressive ratio alcohol self-administration in nonselected Wistars. In the reinstatement tests, the compound did not have effects on cue-, footshock stress- and yohimbine-induced relapse. Conversely, URB597 completely abolished the anxiogenic response measured during withdrawal after an acute IP administration of alcohol (3.0 g/kg). Rimonabant (0.0, 0.3, 1.0 and 3.0 mg/kg) significantly reduced ethanol self-administration. Conclusions Results demonstrate that activation of the endocannabinoid anandamide system by selective inhibition of FAAH does not increase alcohol abuse risks but does reduce anxiety associated to alcohol withdrawal. We thus can speculate that medication based on the use of endocannabinoid system modulators such as URB597 may offer important advantages compared to treatment with direct CB1 receptor activators.
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antidepressant like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress
Biological Psychiatry, 2007Co-Authors: Marco Bortolato, Andrea Duranti, Andrea Tontini, Giorgio Tarzia, Regina A Mangieri, Jin Fu, Oliver Arguello, Daniele PiomelliAbstract:BACKGROUND: The endocannabinoid anandamide may be involved in the regulation of emotional reactivity. In particular, it has been shown that pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of anandamide, elicits anxiolytic-like and antidepressant-like effects in rodents. METHODS: We investigated the impact of chronic treatment with the selective FAAH inhibitor, URB597 (also termed KDS-4103), on the outcomes of the chronic mild stress (CMS) in rats, a behavioral model with high isomorphism to human depression. RESULTS: Daily administration of URB597 (.3 mg kg(-1), intraperitoneal [IP]) for 5 weeks corrected the reduction in body weight gain and sucrose intake induced by CMS. The antidepressant imipramine (20 mg kg(-1), once daily, IP) produced a similar response, whereas lower doses of URB597 were either marginally effective (.1 mg kg(-1)) or ineffective (.03 mg kg(-1)). Treatment with URB597 (.3 mg kg(-1)) resulted in a profound inhibition of brain FAAH activity in both CMS-exposed and control rats. Furthermore, the drug regimen increased anandamide levels in midbrain, striatum, and thalamus. CONCLUSIONS: URB597 exerts antidepressant-like effects in a highly specific and predictive animal model of depression. These effects may depend on the ability of URB597 to enhance anandamide signaling in select regions of the brain.
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the fatty acid amide hydrolase inhibitor URB597 cyclohexylcarbamic acid 3 carbamoylbiphenyl 3 yl ester reduces neuropathic pain after oral administration in mice
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Roberto Russo, Andrea Duranti, Andrea Tontini, Giorgio Tarzia, Jesse Loverme, Giovanna La Rana, Timothy R Compton, Jeff A Parrott, Antonio Calignano, Daniele PiomelliAbstract:Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of bioactive fatty acid ethanolamides, such as the endogenous cannabinoid agonist anandamide. Genetic deletion of the faah gene in mice elevates brain anandamide levels and amplifies the antinociceptive effects of this compound. Likewise, pharmacological blockade of FAAH activity reduces nocifensive behavior in animal models of acute and inflammatory pain. In the present study, we investigated the effects of the selective FAAH inhibitor URB597 (KDS-4103, cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester) in the mouse chronic constriction injury (CCI) model of neuropathic pain. Oral administration of URB597 (1–50 mg/kg, once daily) for 4 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single i.p. administration of the cannabinoid CB 1 receptor antagonist rimonabant (1 mg/kg). The antihyperalgesic effects of URB597 were accompanied by a reduction in plasma extravasation induced by CCI, which was prevented by rimonabant (1 mg/kg i.p.) and attenuated by the CB 2 antagonist SR144528 (1 mg/kg i.p.). Oral dosing with URB597 achieved significant, albeit transient, drug levels in plasma, inhibited brain FAAH activity, and elevated spinal cord anandamide content. The results provide new evidence for a role of the endocannabinoid system in pain modulation and reinforce the proposed role of FAAH as a target for analgesic drug development.
Vincenzo Di Marzo - One of the best experts on this subject based on the ideXlab platform.
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endocannabinoids in amygdala and nucleus accumbens mediate social play reward in adolescent rats
The Journal of Neuroscience, 2012Co-Authors: Viviana Trezza, Ruth Damsteegt, Antonia Manduca, Linda W M Van Kerkhof, Jeroen R Pasterkamp, Patrizia Campolongo, Yeping Zhou, Stefania Petrosino, Vincenzo Cuomo, Vincenzo Di MarzoAbstract:The brain endocannabinoid system plays a crucial role in emotional processes. We have previously identified an important role for endocannabinoids in social play behavior, a highly rewarding form of social interaction in adolescent rats. Here, we tested the hypothesis that endocannabinoid modulation of social play behavior occurs in brain regions implicated in emotion and motivation. Social play increased levels of the endocannabinoid anandamide in the amygdala and nucleus accumbens (NAc), but not in prefrontal cortex or hippocampus of 4- to 5-week-old male Wistar rats. Furthermore, social play increased phosphorylation of CB1 cannabinoid receptors in the amygdala. Systemic administration of the anandamide hydrolysis inhibitor URB597 increased social play behavior, and augmented the associated elevation in anandamide levels in the amygdala, but not the NAc. Infusion of URB597 into the basolateral amygdala (BLA) increased social play behavior, and blockade of BLA CB1 cannabinoid receptors with the antagonist/inverse agonist SR141716A prevented the play-enhancing effects of systemic administration of URB597. Infusion of URB597 into the NAc also increased social play, but blockade of NAc CB1 cannabinoid receptors did not antagonize the play-enhancing effects of systemic URB597 treatment. Last, SR141716A did not affect social play after infusion into the core and shell subregions of the NAc, while it reduced social play when infused into the BLA. These data show that increased anandamide signaling in the amygdala and NAc augments social play, and identify the BLA as a prominent site of action for endocannabinoids to modulate the rewarding properties of social interactions in adolescent rats.
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elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type
Journal of Pharmacology and Experimental Therapeutics, 2006Co-Authors: Sabatino Maione, Stefania Petrosino, Enza Palazzo, Vito De Novellis, Luigia Cristino, Tiziana Bisogno, Marta Valenti, V Guglielmotti, Francesco Rossi, Vincenzo Di MarzoAbstract:In the ventrolateral periaqueductal gray (PAG), activation of excitatory output neurons projecting monosynaptically to OFF cells in the rostral ventromedial medulla (RVM) causes antinociceptive responses and is under the control of cannabinoid receptor type-1 (CB1) and vanilloid transient receptor potential vanilloid type 1 (TRPV1) receptors. We studied in healthy rats the effect of elevation of PAG endocannabinoid [anandamide and 2-arachidonoylglycerol (2-AG)] levels produced by intra-PAG injections of the inhibitor of fatty acid amide hydrolase URB597 [cyclohexylcarbamic acid-3′-carbamoyl-biphenyl-3-yl ester] on 1) nociception in the “plantar test” and 2) spontaneous and tail-flick-related activities of RVM neurons. Depending on the dose or time elapsed since administration, URB597 (0.5–2.5 nmol/rat) either suppressed or increased thermal nociception via TRPV1 or CB1 receptors, respectively. TRPV1 or cannabinoid receptor agonists capsaicin (6 nmol) and ( R )-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3,- de ]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate [WIN55,212-2 (4 nmol)] also suppressed or enhanced nociception, respectively. URB597 dose dependently enhanced PAG anandamide and 2-AG levels, with probable subsequent activation of TRPV1/CB1 receptors and only CB1 receptors, respectively. The TRPV1-mediated antinociception and CB1-mediated nociception caused by URB597 correlated with enhanced or reduced activity of RVM OFF cells, suggesting that these effects occur via stimulation or inhibition of excitatory PAG output neurons, respectively. Accordingly, several ventrolateral PAG neurons were found by immunohistochemistry to coexpress TRPV1 and CB1 receptors. Finally, at the highest doses tested, URB597 (4 nmol/rat) and, as previously reported, WIN55,212-2 (25–100 nmol) also caused CB1-mediated analgesia, correlating with stimulation (possibly disinhibition) of RVM OFF cells. Thus, endocannabinoids affect the descending pathways of pain control by acting at either CB1 or TRPV1 receptors in healthy rats.
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A role for vanilloid receptor 1 (TRPV1) and endocannabinnoid signalling in the regulation of spontaneous and L-DOPA induced locomotion in normal and reserpine-treated rats
Neuropharmacology, 2006Co-Authors: Joohyung Lee, Vincenzo Di Marzo, Jonathan M. BrotchieAbstract:Abstract Although most commonly associated with actions at cannabinoid CB1 receptors on the extracellular surface of the plasma membrane, the endocannabinoid anandamide (AEA) is also transported into the cell, by the putative anandamide membrane transporter (AMT), and activates the vanilloid receptor 1 (TRPV1) at an intracellular site. AEA is then inactivated by fatty acid amide hydrolase (FAAH). As systemic administration of TRPV1 ligands reduces locomotor activity in normal rodents, we hypothesised that activation of TRPV1 by endocannabinoids could play a role in the control of voluntary movement and that such actions could be regulated by AMT and FAAH. Motor activity was assessed in normal, in reserpine-treated, and in reserpine-treated rats treated with L-DOPA. In normal rats, the TRPV1 agonist capsaicin (1 mg/kg) or the FAAH inhibitor URB597 (10 mg/kg) caused a significant reduction in movement in both the horizontal (locomotion) and vertical (rearing) planes (−45% and −53% respectively with capsaicin; −33% and −37% for URB597). Capsaicin-induced hypolocomotion was attenuated by the TRPV1 antagonist, capsazepine. There was no effect of capsaicin, URB597 or the AMT inhibitor OMDM-2 on motor activity in reserpine-treated rats. L-DOPA treatment of reserpine-treated rats elicited high levels of motor activity in both the horizontal and vertical planes. Horizontal activity was attenuated by capsaicin (1 mg/kg, −60%), but not by URB597 (10 mg/kg) or OMDM-2 (5 mg/kg). Vertical activity was attenuated by capsaicin (1 mg/kg, −61%) and by URB597 (10 mg/kg, −54%), but not by OMDM-2. These data suggest that activation of the TRPV1 system can suppress spontaneous locomotion in normal animals and modulates several L-DOPA-induced behaviours in reserpine-treated rats.
Andrea Tontini - One of the best experts on this subject based on the ideXlab platform.
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Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat
Psychopharmacology, 2008Co-Authors: Andrea Cippitelli, Andrea Duranti, Daniele Piomelli, Andrea Tontini, Nazzareno Cannella, Simone Braconi, Ainhoa Bilbao, Fernando Rodríguez Defonseca, Roberto CiccocioppoAbstract:Rationale A major clinical concern with the use of cannabinoid receptor 1 (CB1) direct agonists is that these compounds increase alcohol drinking and drug abuse-related behaviours. As an alternative approach, CB1-receptor-mediated activity can be facilitated by increasing anandamide levels with the use of hydrolase fatty acid amide hydrolase (FAAH) inhibitors. Objective Using the selective FAAH inhibitor URB597, we investigated whether activation of the endogenous cannabinoid tone increases alcohol abuse liability, as what happens with the CB1 receptor direct agonists. Materials and methods URB597 was tested on alcohol self-administration in Wistar rats and on homecage alcohol drinking in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. In Wistar rats, URB597 effects on alcohol-induced anxiety and on stress-, yohimbine- and cue-induced reinstatement of alcohol seeking were also evaluated. For comparison, the effect of the CB1 receptor antagonist rimonabant on ethanol self-administration was also tested. Results Under our experimental condition, intraperitoneal (IP) administration of URB597 (0.0, 0.3 and 1.0 mg/kg) neither increased voluntary homecage alcohol drinking in msP rats nor facilitated fixed ratio 1 and progressive ratio alcohol self-administration in nonselected Wistars. In the reinstatement tests, the compound did not have effects on cue-, footshock stress- and yohimbine-induced relapse. Conversely, URB597 completely abolished the anxiogenic response measured during withdrawal after an acute IP administration of alcohol (3.0 g/kg). Rimonabant (0.0, 0.3, 1.0 and 3.0 mg/kg) significantly reduced ethanol self-administration. Conclusions Results demonstrate that activation of the endocannabinoid anandamide system by selective inhibition of FAAH does not increase alcohol abuse risks but does reduce anxiety associated to alcohol withdrawal. We thus can speculate that medication based on the use of endocannabinoid system modulators such as URB597 may offer important advantages compared to treatment with direct CB1 receptor activators.
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antidepressant like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress
Biological Psychiatry, 2007Co-Authors: Marco Bortolato, Andrea Duranti, Andrea Tontini, Giorgio Tarzia, Regina A Mangieri, Jin Fu, Oliver Arguello, Daniele PiomelliAbstract:BACKGROUND: The endocannabinoid anandamide may be involved in the regulation of emotional reactivity. In particular, it has been shown that pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of anandamide, elicits anxiolytic-like and antidepressant-like effects in rodents. METHODS: We investigated the impact of chronic treatment with the selective FAAH inhibitor, URB597 (also termed KDS-4103), on the outcomes of the chronic mild stress (CMS) in rats, a behavioral model with high isomorphism to human depression. RESULTS: Daily administration of URB597 (.3 mg kg(-1), intraperitoneal [IP]) for 5 weeks corrected the reduction in body weight gain and sucrose intake induced by CMS. The antidepressant imipramine (20 mg kg(-1), once daily, IP) produced a similar response, whereas lower doses of URB597 were either marginally effective (.1 mg kg(-1)) or ineffective (.03 mg kg(-1)). Treatment with URB597 (.3 mg kg(-1)) resulted in a profound inhibition of brain FAAH activity in both CMS-exposed and control rats. Furthermore, the drug regimen increased anandamide levels in midbrain, striatum, and thalamus. CONCLUSIONS: URB597 exerts antidepressant-like effects in a highly specific and predictive animal model of depression. These effects may depend on the ability of URB597 to enhance anandamide signaling in select regions of the brain.
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the fatty acid amide hydrolase inhibitor URB597 cyclohexylcarbamic acid 3 carbamoylbiphenyl 3 yl ester reduces neuropathic pain after oral administration in mice
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Roberto Russo, Andrea Duranti, Andrea Tontini, Giorgio Tarzia, Jesse Loverme, Giovanna La Rana, Timothy R Compton, Jeff A Parrott, Antonio Calignano, Daniele PiomelliAbstract:Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of bioactive fatty acid ethanolamides, such as the endogenous cannabinoid agonist anandamide. Genetic deletion of the faah gene in mice elevates brain anandamide levels and amplifies the antinociceptive effects of this compound. Likewise, pharmacological blockade of FAAH activity reduces nocifensive behavior in animal models of acute and inflammatory pain. In the present study, we investigated the effects of the selective FAAH inhibitor URB597 (KDS-4103, cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester) in the mouse chronic constriction injury (CCI) model of neuropathic pain. Oral administration of URB597 (1–50 mg/kg, once daily) for 4 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single i.p. administration of the cannabinoid CB 1 receptor antagonist rimonabant (1 mg/kg). The antihyperalgesic effects of URB597 were accompanied by a reduction in plasma extravasation induced by CCI, which was prevented by rimonabant (1 mg/kg i.p.) and attenuated by the CB 2 antagonist SR144528 (1 mg/kg i.p.). Oral dosing with URB597 achieved significant, albeit transient, drug levels in plasma, inhibited brain FAAH activity, and elevated spinal cord anandamide content. The results provide new evidence for a role of the endocannabinoid system in pain modulation and reinforce the proposed role of FAAH as a target for analgesic drug development.
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The Fatty Acid Amide Hydrolase Inhibitor URB597 (Cyclohexylcarbamic Acid 3′-Carbamoylbiphenyl-3-yl Ester) Reduces Neuropathic Pain after Oral Administration in Mice
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Roberto Russo, Andrea Duranti, Andrea Tontini, Giorgio Tarzia, Jesse Loverme, Giovanna La Rana, Timothy R Compton, Jeff A Parrott, Marco Mor, Antonio CalignanoAbstract:Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of bioactive fatty acid ethanolamides, such as the endogenous cannabinoid agonist anandamide. Genetic deletion of the faah gene in mice elevates brain anandamide levels and amplifies the antinociceptive effects of this compound. Likewise, pharmacological blockade of FAAH activity reduces nocifensive behavior in animal models of acute and inflammatory pain. In the present study, we investigated the effects of the selective FAAH inhibitor URB597 (KDS-4103, cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester) in the mouse chronic constriction injury (CCI) model of neuropathic pain. Oral administration of URB597 (1-50 mg/kg, once daily) for 4 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single i.p. administration of the cannabinoid CB(1) receptor antagonist rimonabant (1 mg/kg). The antihyperalgesic effects of URB597 were accompanied by a reduction in plasma extravasation induced by CCI, which was prevented by rimonabant (1 mg/kg i.p.) and attenuated by the CB(2) antagonist SR144528 (1 mg/kg i.p.). Oral dosing with URB597 achieved significant, albeit transient, drug levels in plasma, inhibited brain FAAH activity, and elevated spinal cord anandamide content. The results provide new evidence for a role of the endocannabinoid system in pain modulation and reinforce the proposed role of FAAH as a target for analgesic drug development.
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the fatty acid amide hydrolase inhibitor URB597 does not affect triacylglycerol hydrolysis in rat tissues
Pharmacological Research, 2006Co-Authors: Jaso R Clappe, Andrea Duranti, Andrea Tontini, Giorgio Tarzia, Daniele PiomelliAbstract:The O-arylcarbamate URB597 (cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester; also referred to as KDS-4103) is a potent inhibitor of fatty-acid amide hydrolase (FAAH), an intracellular serine hydrolase responsible for the inactivation of the endogenous cannabinoid anandamide. URB597 demonstrates a remarkable degree of selectivity for FAAH over other serine hydrolases (e.g. cholinesterases) or other components of the endocannabinoid system (e.g. cannabinoid receptors). However, in a proteomic-based selectivity screen based on the displacement of fluorophosphonate-rhodamine (FPR) from mouse brain proteins, it was recently shown that URB597 prevents FPR binding to triacylglycerol hydrolase (TGH) with a median inhibitory concentration of 192nM. To determine whether this effect correlates with inhibition of TGH activity, we investigated the ability of URB597 to inhibit triolein hydrolysis in rat liver and heart tissues, which are rich in TGH, as well as white adipose tissue (WAT), which is rich in adipose triacylglycerol lipase (TGL) and hormone-sensitive lipase. The results show that URB597 does not affect triolein hydrolysis in any of these tissues at concentrations as high as 10microM, whereas it inhibits FAAH activity at low nanomolar concentrations. Moreover, intraperitoneal (i.p.) administration of URB597 at doses that maximally inhibit FAAH in vivo (0.3-3mgkg(-1)) exerts no effect on triolein hydrolysis and tissue triacylglycerol (TAG) levels in rat liver, heart or WAT. The results indicate that URB597, while potent at inhibiting FAAH, does not affect TGH and TGL activities in rat tissues.
Giorgio Tarzia - One of the best experts on this subject based on the ideXlab platform.
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antidepressant like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress
Biological Psychiatry, 2007Co-Authors: Marco Bortolato, Andrea Duranti, Andrea Tontini, Giorgio Tarzia, Regina A Mangieri, Jin Fu, Oliver Arguello, Daniele PiomelliAbstract:BACKGROUND: The endocannabinoid anandamide may be involved in the regulation of emotional reactivity. In particular, it has been shown that pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of anandamide, elicits anxiolytic-like and antidepressant-like effects in rodents. METHODS: We investigated the impact of chronic treatment with the selective FAAH inhibitor, URB597 (also termed KDS-4103), on the outcomes of the chronic mild stress (CMS) in rats, a behavioral model with high isomorphism to human depression. RESULTS: Daily administration of URB597 (.3 mg kg(-1), intraperitoneal [IP]) for 5 weeks corrected the reduction in body weight gain and sucrose intake induced by CMS. The antidepressant imipramine (20 mg kg(-1), once daily, IP) produced a similar response, whereas lower doses of URB597 were either marginally effective (.1 mg kg(-1)) or ineffective (.03 mg kg(-1)). Treatment with URB597 (.3 mg kg(-1)) resulted in a profound inhibition of brain FAAH activity in both CMS-exposed and control rats. Furthermore, the drug regimen increased anandamide levels in midbrain, striatum, and thalamus. CONCLUSIONS: URB597 exerts antidepressant-like effects in a highly specific and predictive animal model of depression. These effects may depend on the ability of URB597 to enhance anandamide signaling in select regions of the brain.
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the fatty acid amide hydrolase inhibitor URB597 cyclohexylcarbamic acid 3 carbamoylbiphenyl 3 yl ester reduces neuropathic pain after oral administration in mice
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Roberto Russo, Andrea Duranti, Andrea Tontini, Giorgio Tarzia, Jesse Loverme, Giovanna La Rana, Timothy R Compton, Jeff A Parrott, Antonio Calignano, Daniele PiomelliAbstract:Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of bioactive fatty acid ethanolamides, such as the endogenous cannabinoid agonist anandamide. Genetic deletion of the faah gene in mice elevates brain anandamide levels and amplifies the antinociceptive effects of this compound. Likewise, pharmacological blockade of FAAH activity reduces nocifensive behavior in animal models of acute and inflammatory pain. In the present study, we investigated the effects of the selective FAAH inhibitor URB597 (KDS-4103, cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester) in the mouse chronic constriction injury (CCI) model of neuropathic pain. Oral administration of URB597 (1–50 mg/kg, once daily) for 4 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single i.p. administration of the cannabinoid CB 1 receptor antagonist rimonabant (1 mg/kg). The antihyperalgesic effects of URB597 were accompanied by a reduction in plasma extravasation induced by CCI, which was prevented by rimonabant (1 mg/kg i.p.) and attenuated by the CB 2 antagonist SR144528 (1 mg/kg i.p.). Oral dosing with URB597 achieved significant, albeit transient, drug levels in plasma, inhibited brain FAAH activity, and elevated spinal cord anandamide content. The results provide new evidence for a role of the endocannabinoid system in pain modulation and reinforce the proposed role of FAAH as a target for analgesic drug development.
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The Fatty Acid Amide Hydrolase Inhibitor URB597 (Cyclohexylcarbamic Acid 3′-Carbamoylbiphenyl-3-yl Ester) Reduces Neuropathic Pain after Oral Administration in Mice
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Roberto Russo, Andrea Duranti, Andrea Tontini, Giorgio Tarzia, Jesse Loverme, Giovanna La Rana, Timothy R Compton, Jeff A Parrott, Marco Mor, Antonio CalignanoAbstract:Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of bioactive fatty acid ethanolamides, such as the endogenous cannabinoid agonist anandamide. Genetic deletion of the faah gene in mice elevates brain anandamide levels and amplifies the antinociceptive effects of this compound. Likewise, pharmacological blockade of FAAH activity reduces nocifensive behavior in animal models of acute and inflammatory pain. In the present study, we investigated the effects of the selective FAAH inhibitor URB597 (KDS-4103, cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester) in the mouse chronic constriction injury (CCI) model of neuropathic pain. Oral administration of URB597 (1-50 mg/kg, once daily) for 4 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single i.p. administration of the cannabinoid CB(1) receptor antagonist rimonabant (1 mg/kg). The antihyperalgesic effects of URB597 were accompanied by a reduction in plasma extravasation induced by CCI, which was prevented by rimonabant (1 mg/kg i.p.) and attenuated by the CB(2) antagonist SR144528 (1 mg/kg i.p.). Oral dosing with URB597 achieved significant, albeit transient, drug levels in plasma, inhibited brain FAAH activity, and elevated spinal cord anandamide content. The results provide new evidence for a role of the endocannabinoid system in pain modulation and reinforce the proposed role of FAAH as a target for analgesic drug development.
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the fatty acid amide hydrolase inhibitor URB597 does not affect triacylglycerol hydrolysis in rat tissues
Pharmacological Research, 2006Co-Authors: Jaso R Clappe, Andrea Duranti, Andrea Tontini, Giorgio Tarzia, Daniele PiomelliAbstract:The O-arylcarbamate URB597 (cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester; also referred to as KDS-4103) is a potent inhibitor of fatty-acid amide hydrolase (FAAH), an intracellular serine hydrolase responsible for the inactivation of the endogenous cannabinoid anandamide. URB597 demonstrates a remarkable degree of selectivity for FAAH over other serine hydrolases (e.g. cholinesterases) or other components of the endocannabinoid system (e.g. cannabinoid receptors). However, in a proteomic-based selectivity screen based on the displacement of fluorophosphonate-rhodamine (FPR) from mouse brain proteins, it was recently shown that URB597 prevents FPR binding to triacylglycerol hydrolase (TGH) with a median inhibitory concentration of 192nM. To determine whether this effect correlates with inhibition of TGH activity, we investigated the ability of URB597 to inhibit triolein hydrolysis in rat liver and heart tissues, which are rich in TGH, as well as white adipose tissue (WAT), which is rich in adipose triacylglycerol lipase (TGL) and hormone-sensitive lipase. The results show that URB597 does not affect triolein hydrolysis in any of these tissues at concentrations as high as 10microM, whereas it inhibits FAAH activity at low nanomolar concentrations. Moreover, intraperitoneal (i.p.) administration of URB597 at doses that maximally inhibit FAAH in vivo (0.3-3mgkg(-1)) exerts no effect on triolein hydrolysis and tissue triacylglycerol (TAG) levels in rat liver, heart or WAT. The results indicate that URB597, while potent at inhibiting FAAH, does not affect TGH and TGL activities in rat tissues.
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characterization of the fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3 carbamoyl biphenyl 3 yl ester URB597 effects on anandamide and oleoylethanolamide deactivation
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Darren Fegley, Andrea Duranti, Andrea Tontini, Giorgio Tarzia, Silvana Gaetani, Daniele PiomelliAbstract:Fatty acid amide hydrolase (FAAH) is an intracellular serine enzyme that catalyzes the hydrolysis of bioactive fatty acid ethanolamides such as anandamide and oleoylethanolamide (OEA). Genetic deletion of the faah gene in mice elevates brain anandamide levels and amplifies the effects of this endogenous cannabinoid agonist. Here, we show that systemic administration of the selective FAAH inhibitor URB597 (cyclohexyl carbamic acid 3′-carbamoyl-biphenyl-3-yl ester; 0.3 mg/kg i.p.) increases anandamide levels in the brain of rats and wild-type mice but has no such effect in FAAH-null mutants. Moreover, URB597 enhances the hypothermic actions of anandamide (5 mg/kg i.p.) in wild-type mice but not in FAAH-null mice. In contrast, the FAAH inhibitor does not affect anandamide or OEA levels in the rat duodenum at doses that completely inhibit FAAH activity. In addition, URB597 does not alter the hypophagic response elicited by OEA (5 and 10 mg/kg i.p.), which is mediated by activation of peroxisome proliferator-activated receptor type-α. Finally, exogenously administered OEA (5 mg/kg i.p.) was eliminated at comparable rates in wild-type and FAAH -/- mice. Our results indicate that URB597 increases brain anandamide levels and magnifies anandamide responses by inhibiting intracellular FAAH activity. The results also suggest that an enzyme distinct from FAAH catalyzes OEA hydrolysis in the duodenum, where this lipid substance acts as a local satiety factor.
