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NEUROPHARMACOLOGY
Department of Pharmacology (D.F., S.G., D.P.) and Center for the Neurobiology of Learning and Memory (D.P.), University of California, Irvine, California, Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Urbino Carlo Bo, Urbino, Italy (A.D., A.T.G.T.); and Dipartimento Farmaceutico, Università degli Studi di Parma, Parma, Italy (M.M.)
Received October 7, 2004; accepted December 2, 2004.
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Abstract |
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. 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.
; Di Marzo et al., 1994), the satiety factor oleoylethanolamide (OEA) (Rodríguez de Fonseca et al., 2001; Fu et al., 2003), and the analgesic and anti-inflammatory factor palmitoylethanolamide (PEA) (Kuehl et al., 1957; Calignano et al., 1998; Jaggar et al., 1998) are all members of the fatty acid ethanolamide (FAE) family of lipid mediators. FAEs are found in most mammalian tissues, where they are thought to be stored as the phospholipid precursor N-acylphosphatidylethanolamine (Schmid et al., 1996; Piomelli, 2003) and to be produced in a stimulus-dependent manner by activation of an N-acylphosphatidylethanolamine-specific phospholipase D (Okamoto et al., 2004).
After release from cells, polyunsaturated FAEs such as anandamide may be eliminated via a two-step process consisting of high-affinity transport into cells (Di Marzo et al., 1994; Beltramo et al., 1997; Hillard et al., 1997; Fegley et al., 2004; Ortega-Gutierrez et al., 2004) followed by intracellular degradation, catalyzed by fatty acid amide hydrolase (FAAH) (Cravatt and Lichtman, 2002). On the other hand, monounsaturated and saturated FAEs such as OEA and PEA are poor substrates for anandamide transport, and their inactivation may be primarily mediated by intracellular hydrolysis catalyzed by FAAH and/or by a distinct but as-yet-uncharacterized FAE amidase that operates at acid pH values (Ueda et al., 1999, 2001).
Mutant mice lacking the gene encoding for FAAH (faah) have reduced FAE hydrolysis and elevated brain levels of these lipid amides (Cravatt et al., 2001). Furthermore, although FAAH-null mice show signs of enhanced anandamide signaling at cannabinoid receptors (e.g., decreased pain sensation) and increased sensitivity to exogenous anandamide, their overall behavior is similar in other respects to that of wild-type mice (Cravatt et al., 2001; Lichtman et al., 2004). This suggests that drugs targeting FAAH might heighten the tonic actions of anandamide while avoiding unwanted effects due to direct activation of cannabinoid receptors.
We have recently identified a new class of highly selective O-arylcarbamate inhibitors of intracellular FAAH activity (Tarzia et al., 2003; Mor et al., 2004), which exert potent anxiolytic-like (Kathuria et al., 2003) and antihypertensive (Batkai et al., 2004) effects in rodents. Systemic administration of a prototype member of this class, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester), produces profound inhibition of brain FAE hydrolysis in rats, which is accompanied by elevation of brain FAE content and potentiation of anandamide actions (Kathuria et al., 2003). In the present study, we have used FAAH-deficient mice to determine whether these effects of URB597 are due exclusively to inhibition of FAAH activity. In addition, we have examined whether URB597 also amplifies the satiety-inducing actions of OEA (Rodríguez de Fonseca et al., 2001; Gaetani et al., 2003), which are mediated by activation of peroxisome proliferator-activated receptor- (PPAR-) (Fu et al., 2003).
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Materials and Methods |
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Drugs. We prepared anandamide and OEA following standard procedures (Giuffrida et al., 2000) and URB597 as described (Mor et al., 2004). Alternatively, URB597 was prepared through the following procedure. Diimidazol-1-yl methanone and 4-dimethylaminopyridine were added to a stirred solution of cyclohexylamine in dry acetonitrile. After refluxing the reactants for 3 h, 3'-hydroxybiphenyl-3-carboxylic acid amide was added, and the mixture was allowed to react for 6 h, then cooled and concentrated. Purification of the residue by column chromatography and recrystallization gave the desired product as a white solid.
Chemicals. Fatty acyl chlorides [5,8,11,14-eicosatetraenoyl chloride, hexadecanoyl chloride, and 9-(cis)octadecenoyl chloride] were purchased from Nu-Check Prep (Elysian, MN); [2H4]ethanolamine (isotopic atom enrichment 98%) was from Cambridge Isotope Laboratories (Andover, MA).
Synthesis of 2H4-Labeled Standards. Standard 2H4-labeled FAEs were synthesized by the reaction of the corresponding fatty acyl chlorides with 2H4-labeled ethanolamine. Fatty acyl chlorides were dissolved in dichloromethane (10 mg/ml) and allowed to react with 1 equivalent of 2H4-labeled ethanolamine for 15 min at 0 to 4°C. The reaction was stopped by adding purified water. After vigorous stirring and phase separation, the upper aqueous phase was discarded, and the organic phase was washed twice with water to remove unreacted ethanolamine. The reaction results in quantitative formation of 2H4-labeled FAEs, which were concentrated to dryness under a stream of N2 and reconstituted in chloroform at a concentration of 20 mM. FAE solutions were stored at -20°C until use. Identity and chemical purity (>99.9%) of the synthesized FAEs were determined by thin-layer chromatography and high-performance liquid chromatography/mass spectrometry (HPLC/MS). 2-Arachidoloylglycerol (2-AG) and [2H8]2-AG were purchased from Cayman Chemical (Ann Arbor, MI).
Tissue Preparation. Animals were killed with halothane (Halocarbon Laboratories, River Edge, NJ), and tissues were rapidly collected and snap-frozen in cold 2-methylbutane (-50°C). The tissues were thawed in 2 ml of methanol containing 25 pmol [2H4]anandamide and [2H8]2-AG and 500 pmol [2H4]OEA and [2H4]PEA and homogenized. FAEs were extracted with methanol-chloroform (1:2, v/v, 6 ml). The chloroform phase was recovered, evaporated to dryness under a stream of N2, reconstituted in 1 ml of chloroform, and passed through Silica Gel G columns. Briefly, columns were prepared by adding 1 ml of a chloroform Silica Gel G (60-Å 230-400 Mesh ASTM; Whatman, Clifton, NJ) mixture (1:1, v/v) to 5' Pasteur pipets, plugged with glass wool. The samples were loaded onto the columns and washed with 1 ml of chloroform. FAEs were eluted with 2 ml of a chloroform/methanol mixture (9:1, v/v). The eluate was recovered and evaporated to dryness under N2, reconstituted in a mixture of chloroform/methanol (1:3, 80 µl) and transferred to 2.0-ml screw top vials with 0.1-ml glass inserts to be injected into the HPLC/MS.
HPLC/MS Analysis. FAEs were quantified using an isotope dilution HPLC/MS assay in positive ionization mode (Giuffrida et al., 2000).
Enzyme Preparation. Animals were anesthetized with halothane and sacrificed by decapitation. The brain and duodenum were removed and homogenized in ice-cold Tris-HCL (20 mM, 10 vol, pH 7.4) containing 0.32 M sucrose. The homogenates were centrifuged at 800g for 15 min and then at 27,000g for 30 min. The 27,000g pellet was suspended in phosphate-buffered saline (pH = 7.4) and used for FAAH assays. To isolate the acid amidase activity, the pellet was first subjected to two cycles of freezing and thawing and then centrifuged at 105,000g for 60 min (Ueda et al., 2001). Acid amidase activity was analyzed in the supernatant, as described below.
FAE Hydrolysis Assays. We measured FAAH activity at 37°C for 30 min in 0.5 ml of Tris buffer (50 mM, pH 7.5) containing fatty acid-free bovine serum albumin (0.05%), membrane protein (50 µg) and anandamide[ethanolamine-3H] (10,000 dpm, specific activity 20 Ci/mmol; American Radiolabeled Chemicals, St. Louis, MO). We quantified acid amidase activity at 37°C for 30 min in 0.5 ml of sodium phosphate buffer (50 mM, pH 5.0) containing 3 mM dithiothreitol, 0.1% Triton X-100, protein (50 µg), and palmitoyl[ethanolamine-3H] (30,000 dpm, specific activity 20 Ci/mmol; American Radiolabeled Chemicals). After stopping the reactions with chloroform/methanol (1:1, 1 ml), we measured radioactivity in the aqueous layers by liquid scintillation counting.
Body Temperature. We measured rectal temperature using a thermocouple probe (Physitemp Instruments, Inc., Clifton, NJ). All drugs were dissolved in a vehicle of saline/Tween 80/polyethylene glycol (90:5:5) and administered by i.p. injection. URB597 was injected 30 min before anandamide.
Feeding Behavior. Food intake was recorded with an automated system (Scipro Inc., New York, NY) consisting of 24 cages equipped with baskets connected to weight sensors. The baskets contained standard chow pellets and were accessible to the rats or mice through a hole in the wire lid of the cage. Each time food was removed from the basket, the computer recorded the duration of the event, the amount of food retrieved, and the time at which the event occurred. Weight variations were monitored every second, and threshold for an eating episode was set at 0.5 g for rats or 0.1 g for mice and >1 min. The animals were habituated to the test cages for 3 days prior to trials. Experiments began at the onset of the dark phase and lasted 24 h.
Analysis. A detailed meal analysis was performed adopting a minimum inter-response interval separating two meals of 10 min (Burton et al., 1981). Two categories of feeding parameters were distinguished: first meal parameters and average meal parameters (Reidelberger et al., 2001). The first meal parameters included: latency of feeding onset (minutes), the time interval from trial inception to the first eating episode; first meal size (grams per kilogram), amount of food consumed during the first meal; and first post meal interval (minutes), the time interval between end of the first meal and beginning of the second meal. The average meal parameters included: meal size and post meal interval, the average of each meal parameter over all meals during the trial period, calculated for each animal.
Statistical Analysis. Results are expressed as the mean ± S.E.M. Statistical significance was evaluated using the Student's t test or, when appropriate, one-way analysis of variance followed by the Dunnett's test. Body temperature and food intake were analyzed by two-way analysis of variance, using treatments and time as the two factors, followed by Bonferroni post hoc analysis.
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Results |
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Next, we used FAAH-/- mice to examine whether the ability of URB597 to elevate FAE levels in the brain is due to selective inhibition of FAAH activity. As previously reported (Cravatt et al., 2001), brain membranes from FAAH-/- mice contained almost no [3H]anandamide-hydrolyzing activity (Fig. 2a). Accordingly, the FAE content in brain and liver of these mice was significantly elevated (Fig. 2, b–d; Table 2). Administration of URB597 (0.3 mg/kg i.p.) 2 h prior to tissue collection did not further inhibit [3H]anandamide hydrolysis (Fig. 2a) or increase brain FAE levels (Fig. 2, b–d). Furthermore, in agreement with prior results (Kathuria et al., 2003), the drug had no effect on the levels of 2-AG, another endocannabinoid ligand (Mechoulam et al., 1995; Sugiura et al., 1995; Stella et al., 1997) in either wild-type or FAAH-/- mice (data not shown). These findings suggest that FAAH is the primary FAE-hydrolyzing activity targeted by URB597 in the rodent brain.
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URB597 Enhances Anandamide Hypothermia by Inhibiting FAAH. When administered as a drug, anandamide exerts profound hypothermic effects, which are thought to be mediated by activation of hypothalamic CB1 cannabinoid receptors (Rawls et al., 2002). These actions were enhanced by prior administration of URB597 (Kathuria et al., 2003). As shown in Fig. 3a, URB597 (0.3 mg/kg i.p., 30 min before anandamide) intensified the hypothermic effects of a sub-threshold dose of anandamide (5 mg/kg i.p.) in wild-type mice. By contrast, the drug had no effect in FAAH-/- mice (Fig. 3b), indicating that its ability to potentiate the hypothermic actions of anandamide is due to specific inhibition of FAAH activity.
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URB597 Does Not Affect Intestinal FAE Levels. Administration of URB597 (0.3 mg/kg i.p.) inhibited [3H]anandamide hydrolysis (pH 7.5) in the rat duodenum (Fig. 4a) as effectively as it did in brain and liver (Fig. 1a; Table 1). Surprisingly, however, this inhibition was not associated with any significant change in intestinal FAE content (Fig. 4, b–e). Furthermore, anandamide levels in the duodenum of FAAH-/- mice were comparable with those measured in wild-type mice (Fig. 5b). Although the intestinal OEA and PEA contents were 50 to 70% higher in FAAH-/- than wild-type mice (Fig. 5, c and d), these increments were markedly lower than those observed in brain or liver (Fig. 2, b–d; Table 2). These findings suggest that the duodenum may contain additional FAE-hydrolyzing activities distinct from FAAH. One such activity may be PEA-preferring acid amidase (Ueda et al., 1999, 2001). This activity is present in the duodenum of FAAH-/- mice (Fig. 6a) and is not inhibited by URB597 at concentrations that completely block FAAH activity (Fig. 6b).
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URB597 Does Not Potentiate OEA-Induced Hypophagia. Previous studies have shown that OEA inhibits food intake in rats and mice by activating the nuclear receptor PPAR- (Rodríguez de Fonseca et al., 2001; Fu et al., 2003). This effect is prevented when peripheral sensory fibers are removed by treatment with capsaicin or when the vagus nerve is severed below the diaphragm, suggesting that OEA acts by engaging PPAR- localized within the viscera (Rodríguez de Fonseca et al., 2001; Fu et al., 2003). Consistent with these results, administration of OEA (5 and 10 mg/kg i.p.) increased the latency of feeding onset in wild-type mice, a sign of increased satiety, while having no effect on other meal parameters (Fig. 7a; Table 3) (Gaetani et al., 2003). URB597 (0.3 mg/kg i.p.) did not affect the latency of feeding onset when administered alone or 15 min prior to OEA (Fig. 7a). Furthermore, OEA produced a similar elongation of feeding latency in wild-type and FAAH-/- mice (Fig. 7b). Finally, the elimination of exogenously administered OEA was virtually identical in wild-type and FAAH-/- mice. After systemic administration of a 5-mg/kg-dose (i.p.), the time course of OEA elimination from intestinal tissue was comparable in the two genotypes (Fig. 7c).
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Discussion |
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; Tarzia et al., 2003; Mor et al., 2004), elevates anandamide levels in the rat and mouse brain and magnifies the actions of this endocannabinoid ligand through selective blockade of FAAH activity. Two observations support this conclusion. First, administration of URB597 increases anandamide content in the brain of wild-type mice but does not further elevate the high anandamide levels present in the brain of FAAH-null mice. Second, treatment with URB597 heightens the hypothermic response elicited by anandamide in wild-type but not FAAH-deficient mice. These findings underscore the selectivity of URB597 for FAAH and support the conclusion that this enzyme represents the predominant catabolic route for anandamide in the central nervous system (Cravatt et al., 2001).
However, our results also suggest that a quite different scenario may exist in the small intestine, where locally produced anandamide contributes to the regulation of feeding behavior (Gomez et al., 2002) and intestinal motility (Izzo et al., 2001). We found that URB597 does not alter anandamide content in the rat duodenum at a dose that completely abrogates tissue FAAH activity, and anandamide levels in the duodenum of wild-type and FAAH-deficient mice are identical—a striking discrepancy with what is observed in the brain. A parsimonious interpretation of these results is that the rodent small intestine contains, in addition to FAAH, other anandamide-hydrolyzing activities that are not inhibited by URB597. The identity of these hypothetical enzymes is unknown, but one likely candidate is the acid amidase activity recently identified by Ueda et al. (1999, 2001), which we report here to be insensitive to URB597. Although this activity prefers PEA in broken cell preparations, it can also catalyze the hydrolysis of anandamide and OEA, particularly when detergents are excluded from the assay mixture (Ueda et al., 2001).
In addition to anandamide, the small intestine produces large quantities of OEA, which is also implicated in the control of feeding behavior. Administration of this compound causes profound hypophagia in rats and mice (Rodríguez de Fonseca et al., 2001; Fu et al., 2003), which is due to the induction of a state of satiety (Gaetani et al., 2003) and is mediated by activation of the nuclear receptor PPAR- (Fu et al., 2003). Moreover, the intestinal concentrations of OEA are tightly regulated by feeding (Rodríguez de Fonseca et al., 2001) and, after ingestion of a meal, reach values that are sufficient to fully activate PPAR- (Fu et al., 2003). These results suggest that OEA may act as an intestinal satiety hormone (Fu et al., 2003). Here, we have shown that treatment with a maximally effective dose of URB597 fails to increase the intestinal levels of OEA or to enhance its hypophagic effects in rats. We have also found that FAAH-deficient mice, which are supersensitive to anandamide (Cravatt et al., 2001; Fegley et al., 2004), eliminate exogenous OEA as rapidly as do wild-type mice and respond normally to OEA. Together, these findings indicate that FAAH may not be responsible for the deactivation of endogenous OEA in the upper intestine or for its elimination when it is administered as a drug. The possibility that OEA deactivation is mediated by PEA-preferring acid amidase is intriguing and warrants further examination.
In conclusion, our results indicate that URB597 elevates brain anandamide levels and magnifies the pharmacological actions of this endocannabinoid lipid by selectively targeting FAAH activity. The results also suggest that, contrary to what happens in the central nervous system, FAAH does not play a primary role in the deactivation of anandamide and OEA in the small intestine.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: OEA, oleoylethanolamide; PEA, palmitoylethanolamide; FAE, fatty acid ethanolamide; FAAH, fatty acid amide hydrolase; URB597, cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester; PPAR-, peroxisome proliferator-activated receptor type-; HPLC/MS, high-performance liquid chromatography/mass spectrometry; 2-AG, 2-arachidoloylglycerol.
Address correspondence to: Dr. Daniele Piomelli, Department of Pharmacology, 3101 Gillespie NRF, University of California, Irvine CA 92697-4625. E-mail: piomelli{at}uci.edu
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M. Melis, G. Pillolla, A. Luchicchi, A. L. Muntoni, S. Yasar, S. R. Goldberg, and M. Pistis Endogenous Fatty Acid Ethanolamides Suppress Nicotine-Induced Activation of Mesolimbic Dopamine Neurons through Nuclear Receptors J. Neurosci., December 17, 2008; 28(51): 13985 - 13994. [Abstract] [Full Text] [PDF]
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I. A. Khasabova, S. G. Khasabov, C. Harding-Rose, L. G. Coicou, B. A. Seybold, A. E. Lindberg, C. D. Steevens, D. A. Simone, and V. S. Seybold A Decrease in Anandamide Signaling Contributes to the Maintenance of Cutaneous Mechanical Hyperalgesia in a Model of Bone Cancer Pain J. Neurosci., October 29, 2008; 28(44): 11141 - 11152. [Abstract] [Full Text] [PDF]
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L. L. Merritt, B. R. Martin, C. Walters, A. H. Lichtman, and M. I. Damaj The Endogenous Cannabinoid System Modulates Nicotine Reward and Dependence J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 483 - 492. [Abstract] [Full Text] [PDF]
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R. Russo, J. LoVerme, G. La Rana, T. R. Compton, J. Parrott, A. Duranti, A. Tontini, M. Mor, G. Tarzia, A. Calignano, et al. The Fatty Acid Amide Hydrolase Inhibitor URB597 (Cyclohexylcarbamic Acid 3'-Carbamoylbiphenyl-3-yl Ester) Reduces Neuropathic Pain after Oral Administration in Mice J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 236 - 242. [Abstract] [Full Text] [PDF]
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M. Solinas, G. Tanda, Z. Justinova, C. E. Wertheim, S. Yasar, D. Piomelli, S. K. Vadivel, A. Makriyannis, and S. R. Goldberg The Endogenous Cannabinoid Anandamide Produces {delta}-9-Tetrahydrocannabinol-Like Discriminative and Neurochemical Effects That Are Enhanced by Inhibition of Fatty Acid Amide Hydrolase but Not by Inhibition of Anandamide Transport J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 370 - 380. [Abstract] [Full Text] [PDF]
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G. G. Muccioli, C. Xu, E. Odah, E. Cudaback, J. A. Cisneros, D. M. Lambert, M. L. Lopez Rodriguez, S. Bajjalieh, and N. Stella Identification of a Novel Endocannabinoid-Hydrolyzing Enzyme Expressed by Microglial Cells J. Neurosci., March 14, 2007; 27(11): 2883 - 2889. [Abstract] [Full Text] [PDF]
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M. D. Jhaveri, D. Richardson, D. A. Kendall, D. A. Barrett, and V. Chapman Analgesic Effects of Fatty Acid Amide Hydrolase Inhibition in a Rat Model of Neuropathic Pain J. Neurosci., December 20, 2006; 26(51): 13318 - 13327. [Abstract] [Full Text] [PDF]
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R. Mechoulam and D. G. Deutsch Toward an anandamide transporter PNAS, December 6, 2005; 102(49): 17541 - 17542. [Full Text] [PDF]
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