Abstract
The finding of endogenous ligands for cannabinoid receptors, the endocannabinoids, opened a new era in cannabinoid research. It meant that the biological role of cannabinoid signalling could be finally studied by investigating not only the pharmacological actions subsequent to stimulation of cannabinoid receptors by their agonists, but also how the activity of these receptors was regulated under physiological and pathological conditions by varying levels of the endocannabinoids. This in turn meant that the enzymes catalysing endocannabinoid biosynthesis and inactivation had to be identified and characterized, and that selective inhibitors of these enzymes had to be developed to be used as (1) probes to confirm endocannabinoid involvement in health and disease, and (2) templates for the design of new therapeutic drugs. This chapter summarizes the progress achieved in this direction during the 12 years following the discovery of the first endocannabinoid.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Adams IB, Compton DR, Martin BR (1998) Assessment of anandamide interaction with the cannabinoid brain receptor: SR 141716A antagonism studies in mice and autoradiographic analysis of receptor binding in rat brain. J Pharmacol Exp Ther 284:1209–1217
Ahluwalia J, Urban L, Bevan S, Nagy I (2003a) Anandamide regulates neuropeptide release from capsaicin-sensitive primary sensory neurons by activating both the cannabinoid 1 receptor and the vanilloid receptor 1 in vitro. Eur J Neurosci 17:2611–2618
Ahluwalia J, Yaqoob M, Urban L, Bevan S, Nagy I (2003b) Activation of capsaicin-sensitive primary sensory neurones induces anandamide production and release. J Neurochem 84:585–591
Andersson DA, Adner M, Hogestatt ED, Zygmunt PM (2002) Mechanisms underlying tissue selectivity of anandamide and other vanilloid receptor agonists. Mol Pharmacol 62:705–713
Appendino G, Ligresti A, Minassi A, Daddario N, Bisogno T, Di Marzo V (2003) Homologues and isomers of noladin ether, a putative novel endocannabinoid: interaction with rat cannabinoid CB(1) receptors. Bioorg Med Chem Lett 13:43–46
Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Huffman JW, Layward L (2000) Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 404:84–87
Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Makriyannis A, Khanolkar A, Layward L, Fezza F, Bisogno T, Di Marzo V (2001) Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J 15:300–302
Basavarajappa BS, Saito M, Cooper TB, Hungund BL (2000) Stimulation of cannabinoid receptor agonist 2-arachidonylglycerol by chronic ethanol and its modulation by specific neuromodulators in cerebellar granule neurons. Biochim Biophys Acta 1535:78–86
Basavarajappa BS, Saito M, Cooper TB, Hungund BL (2003) Chronic ethanol inhibits the anandamide transport and increases extracellular anandamide levels in cerebellar granule neurons. Eur J Pharmacol 466:73–83
Batkai S, Jarai Z, Wagner JA, Goparaju SK, Varga K, Liu J, Wang L, Mirshahi F, Khanolkar AD, Makriyannis A, Urbaschek R, Garcia N Jr, Sanyal AJ, Kunos G (2001) Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med 7:827–832
Beltramo M, Piomelli D (2000) Carrier-mediated transport and enzymatic hydrolysis of the endogenous cannabinoid 2-arachidonylglycerol. Neuroreport 11:1231–1235
Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D (1997) Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277:1094–1097
Ben-Shabat S, Fride E, Sheskin T, Tamiri T, Rhee MH, Vogel Z, Bisogno T, De Petrocellis L, Di Marzo V, Mechoulam R (1998) An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol 353:23–31
Bensaid M, Gary-Bobo M, Esclangon A, Maffrand JP, Le Fur G, Oury-Donat F, Soubrie P (2003) The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol 63:908–914
Berdyshev EV, Schmid PC, Krebsbach RJ, Schmid HH (2001) Activation of PAF receptors results in enhanced synthesis of 2-arachidonoylglycerol (2-AG) in immune cells. FASEB J 15:2171–2178
Berglund BA, Boring DL, Howlett AC (1999) Investigation of structural analogs of prostaglandin amides for binding to and activation of CB1 and CB2 cannabinoid receptors in rat brain and human tonsils. Adv Exp Med Biol 469:527–533
Berrendero F, Sepe N, Ramos JA, Di Marzo V, Fernandez-Ruiz JJ (1999) Analysis of cannabinoid receptor binding and mRNA expression and endogenous cannabinoid contents in the developing rat brain during late gestation and early postnatal period. Synapse 33:181–191
Berrendero F, Sanchez A, Cabranes A, Puerta C, Ramos JA, Garcia-Merino A, Fernandez-Ruiz J (2001) Changes in cannabinoid CB(1) receptors in striatal and cortical regions of rats with experimental allergic encephalomyelitis, an animal model of multiple sclerosis. Synapse 41:195–202
Bifulco M, Laezza C, Portella G, Vitale M, Orlando P, De Petrocellis L, Di Marzo V (2001) Control by the endogenous cannabinoid system of ras oncogene-dependent tumor growth. FASEB J 15:2745–2747
Bisogno T, Maurelli S, Melck D, De Petrocellis L, Di Marzo V (1997a) Biosynthesis, uptake, and degradation of anandamide and palmitoylethanolamide in leukocytes. J Biol Chem 272:3315–3323
Bisogno T, Sepe N, Melck D, Maurelli S, De Petrocellis L, Di Marzo V (1997b) Biosynthesis, release and degradation of the novel endogenous cannabimimetic metabolite 2-arachidonoylglycerol in mouse neuroblastoma cells. Biochem J 322:671–677
Bisogno T, Melck D, De Petrocellis L, Bobrov MYu, Gretskaya NM, Bezuglov VV, Sitachitta N, Gerwick WH, Di Marzo V (1998) Arachidonoylserotonin and other novel inhibitors of fatty acid amide hydrolase. Biochem Biophys Res Commun 248:515–522
Bisogno T, Berrendero F, Ambrosino G, Cebeira M, Ramos JA, Fernandez-Ruiz JJ, Di Marzo V (1999a) Brain regional distribution of endocannabinoids: implications for their biosynthesis and biological function. Biochem Biophys Res Commun 256:377–380
Bisogno T, Melck D, De Petrocellis L, Di Marzo V (1999b) Phosphatidic acid as the biosynthetic precursor of the endocannabinoid 2-arachidonoylglycerol in intact mouse neuroblastoma cells stimulated with ionomycin. J Neurochem 72:2113–2119
Bisogno T, Melck D, Bobrov MYu, Gretskaya NM, Bezuglov VV, De Petrocellis L, Di Marzo V (2000) N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo. Biochem J 351:817–824
Bisogno T, Maccarrone M, De Petrocellis L, Jarrahian A, Finazzi-Agrò A, Hillard C, Di Marzo V (2001) The uptake by cells of 2-arachidonoylglycerol, an endogenous agonist of cannabinoid receptors. Eur J Biochem 268:1982–1989
Bisogno T, De Petrocellis L, Di Marzo V (2002) Fatty acid amide hydrolase, an enzyme with many bioactive substrates. Possible therapeutic implications. Curr Pharm Des 8:533–547
Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, Matias I, Paul P, Gangadharan U, Hobbs C, Di Marzo V, Doherty, P (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signalling in the brain. J Cell Biol 163:463–468
Boger DL, Sato H, Lerner AE, Hedrick MP, Fecik RA, Miyauchi H, Wilkie GD, Austin BJ, Patricelli MP, Cravatt BF (2000) Exceptionally potent inhibitors of fatty acid amide hydrolase: the enzyme responsible for degradation of endogenous oleamide and anandamide. Proc Natl Acad Sci USA 97:5044–5049
Boger DL, Miyauchi H, Hedrick MP (2001) Alpha-keto heterocycle inhibitors of fatty acid amide hydrolase: carbonyl group modification and alpha-substitution. Bioorg Med Chem Lett 11:1517–1520
Bornheim LM, Kim KY, Chen B, Correia MA (1993) The effect of cannabidiol on mouse hepatic microsomal cytochrome P450-dependent anandamide metabolism. Biochem Biophys Res Commun 197:740–746
Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF (2002) Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science 298:1793–1796
Breivogel CS, Griffin G, Di Marzo V, Martin BR (2001) Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol Pharmacol 60:155–163
Brenowitz SD, Regehr WG (2003) Calcium dependence of retrograde inhibition by endocannabinoids at synapses onto Purkinje cells. J Neurosci 23:6373–6384
Brooks JW, Pryce G, Bisogno T, Jaggar SI, Hankey DJ, Brown P, Bridges D, Ledent C, Bifulco M, Rice AS, Di Marzo V, Baker D (2002) Arvanil-induced inhibition of spasticity and persistent pain: evidence for therapeutic sites of action different from the vanilloid VR1 receptor and cannabinoid CB(1)/CB(2) receptors. Eur J Pharmacol 439:83–92
Cadas H, di Tomaso E, Piomelli D (1997) Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J Neurosci 17:1226–1242
Calignano A, La Rana G, Giuffrida A, Piomelli D (1998) Control of pain initiation by endogenous cannabinoids. Nature 394:277–281
Carrier EJ, Kearn CS, Barkmeier AJ, Breese NM, Yang W, Nithipatikom K, Pfister SL, Campbell WB, Hillard CJ (2004) Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol,which increases proliferation via a CB2 receptor-dependent mechanism. Mol Pharmacol 65:999–1007
Casanova ML, Blazquez C, Martinez-Palacio J, Villanueva C, Fernandez-Acenero MJ, Huffman JW, Jorcano JL, Guzman M (2003) Inhibition of skin tumor growth andangiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 111:43–50
Chemin J, Monteil A, Perez-Reyes E, Nargeot J, Lory P (2001) Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide. EMBO J 20:7033–7040
Chevaleyre V, Castillo PE (2003) Heterosynaptic LTD of hippocampal GABAergic synapses: a novel role of endocannabinoids in regulating excitability. Neuron 38:461–472
Clement AB, Hawkins EG, Lichtman AH, Cravatt BF (2003) Increased seizure susceptibility and proconvulsant activity of anandamide in mice lacking fatty acid amide hydrolase. J Neurosci 23:3916–3923
Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thone-Reineke C, Ortmann S, Tomassoni F, Cervino C, Nisoli E, Linthorst AC, Pasquali R, Lutz B, Stalla GK, Pagotto U (2003) The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 112:423–431
Craib SJ, Ellington HC, Pertwee RG, Ross, RA (2001) A possible role of lipoxygenase in the activation of vanilloid receptors by anandamide in the guinea-pig bronchus. Br J Pharmacol 134:30–37
Cravatt BF, Lichtman AH (2003) Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system. Curr Opin Chem Biol 7:469–475
Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87
Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 98:9371–9376
de Lago E, Fernandez-Ruiz J, Ortega-Gutierrez S, Viso A, Lopez-Rodriguez ML, Ramos JA (2002) UCM707, a potent and selective inhibitor of endocannabinoid uptake, potentiates hypokinetic and antinociceptive effects of anandamide. Eur J Pharmacol 449:99–103
de Lago E, de Miguel R, Lastres-Becker I, Ramos JA, Fernández-Ruiz J (2004a) Involvement of vanilloid-like receptors in the effects of anandamide on motor behavior and nigrostriatal dopaminergic activity: in vivo and in vitro evidence. Brain Res 1007:152–159
de Lago E, Ligresti A, Ortar G, Morera E, Cabranes A, Pryce G, Bifulco M, Baker D, Fernandez-Ruiz J, Di Marzo V (2004b) In vivo pharmacological actions of two novel inhibitors of anandamide cellular uptake. Eur J Pharmacol 484:249–257
De Petrocellis L, Melck D, Ueda N, Maurelli S, Kurahashi Y, Yamamoto S, Marino G, Di Marzo V (1997) Novel inhibitors of brain, neuronal, and basophilic anandamide amidohydrolase. Biochem Biophys Res Commun 231:82–88
De Petrocellis L, Bisogno T, Davis JB, Pertwee RG, Di Marzo V (2000) Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin-like activity. FEBS Lett 483:52–56
De Petrocellis L, Bisogno T, Maccarrone M, Davis JB, Finazzi-Agrò A, Di Marzo V (2001) The activity of anandamide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabolism. J Biol Chem 276:12856–12863
Denovan-Wright EM, Robertson HA (2000) Cannabinoid receptor messenger RNA levels decrease in a subset of neurons of the lateral striatum, cortex and hippocampus of transgenic Huntington’s disease mice. Neuroscience 98:705–713
Deutsch DG, Lin S, Hill WA, Morse KL, Salehani D, Arreaza G, Omeir RL, Makriyannis A (1997a) Fatty acid sulfonyl fluorides inhibit anandamide metabolism and bind to the cannabinoid receptor. Biochem Biophys Res Commun 231:217–221
Deutsch DG, Omeir R, Arreaza G, Salehani D, Prestwich GD, Huang Z, Howlett A (1997b) Methyl arachidonyl fluorophosphonate: a potent irreversible inhibitor of anandamide amidase. Biochem Pharmacol 53:255–260
Deutsch DG, Glaser ST, Howell JM, Kunz JS, Puffenbarger RA, Hillard CJ, Abumrad N (2001) The cellular uptake of anandamide is coupled to its breakdown by fatty-acid amide hydrolase. J Biol Chem 276:6967–6973
Deutsch DG, Ueda N, Yamamoto S (2002) The fatty acid amide hydrolase (FAAH). Prostaglandins Leukot Essent Fatty Acids 66:201–210
Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949
Di Marzo V, Fontana A (1995) Anandamide, an endogenous cannabinomimetic eicosanoid:’ killing two birds with one stone’. Prostaglandins Leukot Essent Fatty Acids 53:1–11
Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz JC, Piomelli D (1994) Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372:686–691
Di Marzo V, De Petrocellis L, Sepe N, Buono A (1996a) Biosynthesis of anandamide and related acylethanolamides in mouse J774 macrophages and N18 neuroblastoma cells. Biochem J 316:977–984
Di Marzo V, De Petrocellis L, Sugiura T, Waku K (1996b) Potential biosynthetic connections between the two cannabimimetic eicosanoids, anandamide and 2-arachidonoylglycerol, in mouse neuroblastoma cells. Biochem Biophys Res Commun 227:281–288
Di Marzo V, Bisogno T, Sugiura T, Melck D, De Petrocellis L (1998a) The novel endogenous cannabinoid 2-arachidonoylglycerol is inactivated by neuronal-and basophil-like cells: connections with anandamide. Biochem J 331:15–19
Di Marzo V, Melck D, Bisogno T, De Petrocellis L (1998b) Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci 21:521–528
Di Marzo V, Bisogno T, De Petrocellis L, Melck D, Orlando P, Wagner JA, Kunos G (1999a) Biosynthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in circulating and tumoral macrophages. Eur J Biochem 264:258–267
Di Marzo V, De Petrocellis L, Bisogno T, Melck D (1999b) Metabolism of anandamide and 2-arachidonoylglycerol: an historical overview and some recent developments. Lipids 34:319–325
Di Marzo V, Breivogel CS, Tao Q, Bridgen DT, Razdan RK, Zimmer AM, Zimmer A, Martin, BR (2000a) Levels, metabolism, and pharmacological activity of anandamide in CB(1) cannabinoid receptor knockout mice: evidence for non-CB(1), non-CB(2) receptor-mediated actions of anandamide in mouse brain. J Neurochem 75:2434–2444
Di Marzo V, Hill MP, Bisogno T, Crossman AR, Brotchie JM (2000b) Enhanced levels of endogenous cannabinoids in the globus pallidus are associated with a reduction in movement in an animal model of Parkinson’s disease. FASEB J 14:1432–1438
Di Marzo V, Bisogno T, De Petrocellis L (2001a) Anandamide: some like it hot. Trends Pharmacol Sci 22:346–349
Di Marzo V, Bisogno T, De Petrocellis L, Brandi I, Jefferson RG, Winckler L, Davis JB, Dasse O, Mahadevan A, Razdan RK, Martin BR (2001b) Highly selective CB(1) cannabinoid receptor ligands and novel CB(1)/VR(1) vanilloid receptor “hybrid” ligands. Biochem Biophys Res Commun 281:444–451
Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G (2001c) Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410:822–825
Di Marzo V, Lastres-Becker I, Bisogno T, De Petrocellis L, Milone A, Davis JB, Fernandez-Ruiz JJ (2001d) Hypolocomotor effects in rats of capsaicin and two long chain capsaicin homologues. Eur J Pharmacol 420:123–131
Di Marzo V, Blumberg PM, Szallasi A (2002a) Endovanilloid signaling in pain. Curr Opin Neurobiol 12:372–379
Di Marzo V, De Petrocellis L, Fezza F, Ligresti A, Bisogno T (2002b) Anandamide receptors. Prostaglandins Leukot Essent Fatty Acids 66:377–391
Di Marzo V, Griffin G, De Petrocellis L, Brandi I, Bisogno T, Williams W, Grier MC, Kulasegram S, Mahadevan A, Razdan RK, Martin BR (2002c) A structure/activity relationship study on arvanil, an endocannabinoid and vanilloid hybrid. J Pharmacol Exp Ther 300:984–991
Di Marzo V, Bifulco M, De Petrocellis L (2004) The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 3:771–784
Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi S, Kathuria S, Piomelli D (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA 99:10819–10824
Edgemond WS, Hillard CJ, Falck JR, Kearn CS, Campbell, WB (1998) Human platelets and polymorphonuclear leukocytes synthesize oxygenated derivatives of arachidonylethanolamide (anandamide): their affinities for cannabinoid receptors and pathways of inactivation. Mol Pharmacol 54:180–188
Egertova M, Giang DK, Cravatt BF, Elphick MR (1998) A new perspective on cannabinoid signalling: complementary localization of fatty acid amide hydrolase and the CB1 receptor in rat brain. Proc R Soc Lond B Biol Sci 265:2081–2085
Evans RM, Scott RH, Ross RA (2004) Multiple actions of anandamide on neonatal rat cultured sensory neurones. Br J Pharmacol 141:1223–1233
Fezza F, Bisogno T, Minassi A, Appendino G, Mechoulam R, Di Marzo V (2002) Noladin ether, a putative novel endocannabinoid: inactivation mechanisms and a sensitive method for its quantification in rat tissues. FEBS Lett 513:294–298
Fowler CJ, Tiger G, Lopez-Rodriguez ML, Viso A, Ortega-Gutierrez S, Ramos JA (2003) Inhibition of fatty acid amidohydrolase, the enzyme responsible for the metabolism of the endocannabinoid anandamide, by analogues of arachidonoyl-serotonin. J Enzyme Inhib Med Chem 18:225–231
Fowler CJ, Tiger G, Ligresti A, López-Rodríguez ML, Di Marzo V (2004) Selective inhibition of anandamide cellular uptake versus enzymatic hydrolysis—a difficult issue to handle. Eur J Pharmacol 492:1–11
Franklin A, Parmentier-Batteur S, Walter L, Greenberg DA, Stella N (2003) Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. J Neurosci 23:7767–7775
Galve-Roperh I, Sanchez C, Cortes ML, del Pulgar TG, Izquierdo M, Guzman M (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 6:313–319
Glaser ST, Abumrad NA, Fatade F, Kaczocha M, Studholme KM, Deutsch DG (2003) Evidence against the presence of an anandamide transporter. Proc Natl Acad Sci USA 100:4269–4274
Goparaju SK, Ueda N, Taniguchi K, Yamamoto S (1999) Enzymes of porcine brain hydrolyzing 2-arachidonoylglycerol, an endogenous ligand of cannabinoid receptors. Biochem Pharmacol 57:417–423
Guo J, Ikeda SR (2004) Endocannabinoids modulate N-type calcium channels and G-protein coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons. Mol Pharmacol 65:665–674
Hajos N, Freund TF (2002) Pharmacological separation of cannabinoid sensitive receptors on hippocampal excitatory and inhibitory fibers. Neuropharmacology 43:503–510
Hajos N, Ledent C, Freund TF (2001) Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience 106:1–4
Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (-)delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95:8268–8273
Hansen HS, Lauritzen L, Moesgaard B, Strand AM, Hansen HH (1998) Formation of N-acylphosphatidylethanolamines and N-acetyl-ethanolamines: proposed role in neurotoxicity. Biochem Pharmacol 55:719–725
Hanus L, Abu-Lafi S, Fride E, Breuer A, Vogel Z, Shalev DE, Kustanovich I, Mechoulam R (2001) 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc Natl Acad Sci USA 98:3662–3665
Hiley CR, Ford WR (2004) Cannabinoid pharmacology in the cardiovascular system: potential protective mechanisms through lipid signalling. Biol Rev Camb Philos Soc 79:187–205
Hillard CJ, Jarrahian A (2000) The movement of N-arachidonoylethanolamine (anandamide) across cellular membranes. Chem Phys Lipids 108:123–134
Hillard CJ, Jarrahian A (2003) Cellular accumulation of anandamide: consensus and controversy. Br J Pharmacol 140:802–808
Hillard CJ, Edgemond WS, Jarrahian A, Campbell WB (1997) Accumulation of N-arachidonoylethanolamine (anandamide) into cerebellar granule cells occurs via facilitated diffusion. J Neurochem 69:631–638
Ho SY, Delgado L, Storch J (2002) Monoacylglycerol metabolism in human intestinal Caco-2 cells: evidence for metabolic compartmentation and hydrolysis. J Biol Chem 277:1816–1823
Horrocks LA (1989) Sources for brain arachidonic acid uptake and turnover in glycerophospholipids. Ann N Y Acad Sci 559:17–24
Huang SM, Bisogno T, Petros TJ, Chang SY, Zavitsanos PA, Zipkin RE, Sivakumar R, Coop A, Maeda DY, De Petrocellis L, Burstein S, Di Marzo V, Walker JM (2001) Identification of a new class of molecules, the arachidonyl amino acids, and characterization of one member that inhibits pain. J Biol Chem 276:42639–42644
Huang SM, Bisogno T, Trevisani M, Al-Hayani A, De Petrocellis L, Fezza F, Tognetto M, Petros TJ, Krey JF, Chu CJ, Miller JD, Davies SN, Geppetti P, Walker JM, Di Marzo V (2002) An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc Natl Acad Sci USA 99:8400–8405
Hwang SW, Cho H, Kwak J, Lee SY, Kang CJ, Jung J, Cho S, Min KH, Suh YG, Kim D, Oh U (2000) Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci USA 97:6155–6160
Izzo AA, Fezza F, Capasso R, Bisogno T, Pinto L, Iuvone T, Esposito G, Mascolo N, Di Marzo V, Capasso F (2001) Cannabinoid CB1-receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation. Br J Pharmacol 134:563–570
Izzo AA, Capasso F, Costagliola A, Bisogno T, Marsicano G, Ligresti A, Matias I, Capasso R, Pinto L, Borrelli F, Cecio A, Lutz B, Mascolo N, Di Marzo V (2003) An endogenous cannabinoid tone attenuates cholera toxin-induced fluid accumulation in mice. Gastroenterology 125:765–774
Jarai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, Zimmer AM, Bonner TI, Buckley NE, Mezey E, Razdan RK, Zimmer A, Kunos G (1999) Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci USA 96:14136–14141
Jarai Z, Wagner JA, Goparaju SK, Wang L, Razdan RK, Sugiura T, Zimmer AM, Bonner TI, Zimmer A, Kunos G (2000) Cardiovascular effects of 2-arachidonoyl glycerol in anesthetized mice. Hypertension 35:679–684
Jarrahian A, Manna S, Edgemond WS, Campbell WB, Hillard CJ (2000) Structure-activity relationships among N-arachidonylethanolamine (anandamide) head group analogues for the anandamide transporter. J Neurochem 74:2597–2606
Jordt SE, Julius D (2002) Molecularbasis for species-specific sensitivity to “hot” chilipeppers. Cell 108:421–430
Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Hogestatt ED, Meng ID, Julius D (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427:260–265
Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C (1997) cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase. Evolutionary relationship to esterases, lysophospholipases, and haloperoxidases. J Biol Chem 272:27218–27223
Karlsson M, Reue K, Xia YR, Lusis AJ, Langin D, Tornqvist H, Holm C (2001) Exon-intron organization and chromosomal localization of the mouse monoglyceride lipase gene. Gene 272:11–18
Kathuria S, Gaetani S, Fegley D, Valino F, Duranti A, Tontini A, Mor M, Tarzia G, La Rana G, Calignano A, Giustino A, Tattoli M, Palmery M, Cuomo V, Piomelli D (2003) Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9:76–81
Kim J, Isokawa M, Ledent C, Alger BE (2002) Activation of muscarinic acetylcholine receptors enhances the release of endogenous cannabinoids in the hippocampus. J Neurosci 22:10182–10191
Kirkham TC, Williams CM, Fezza F, Di Marzo V (2002) Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol 136:550–557
Kondo S, Kondo H, Nakane S, Kodaka T, Tokumura A, Waku K, Sugiura T (1998) 2-Arachidonoylglycerol, an endogenous cannabinoid receptor agonist: identification as one of the major species of monoacylglycerols in various rat tissues, and evidence for its generation through Ca2+-dependent and-independent mechanisms. FEBS Lett 429:152–156
Koutek B, Prestwich GD, Howlett AC, Chin SA, Salehani D, Akhavan N, Deutsch DG (1994) Inhibitors of arachidonoyl ethanolamide hydrolysis. J Biol Chem 269:22937–22940
Kozak KR, Marnett LJ (2002) Oxidative metabolism of endocannabinoids. Prostaglandins Leukot Essent Fatty Acids 66:211–220
Kozak KR, Crews BC, Ray JL, Tai HH, Morrow JD, Marnett LJ (2001) Metabolism of prostaglandin glycerol esters and prostaglandin ethanolamides in vitro and in vivo. J Biol Chem 276:36993–36998
Kozak KR, Gupta RA, Moody JS, Ji C, Boeglin WE, DuBois RN, Brash AR, Marnett LJ (2002) 15-Lipoxygenase metabolism of 2-arachidonylglycerol. Generation of a peroxisome proliferator-activated receptor alpha agonist. J Biol Chem 277:23278–23286
Lambert DM, Vandevoorde S, Jonsson KO, Fowler CJ (2002) The palmitoylethanolamide family: a new class of anti-inflammatory agents? Curr Med Chem 9:663–674
Lastres-Becker I, Fezza F, Cebeira M, Bisogno T, Ramos JA, Milone A, Fernandez-Ruiz J, Di Marzo V (2001) Changes in endocannabinoid transmission in the basal ganglia in a rat model of Huntington’s disease. Neuroreport 12:2125–2129
Lichtman AH, Hawkins EG, Griffin G, Cravatt BF (2002) Pharmacological activity of fatty acid amides is regulated, but not mediated, by fatty acid amide hydrolase in vivo. J Pharmacol Exp Ther 302:73–79
Ligresti A, Bisogno T, Matias I, De Petrocellis L, Cascio MG, Cosenza V, D’argenio G, Scaglione G, Bifulco M, Sorrentini I, Di Marzo V (2003) Possible endocannabinoid control of colorectal cancer growth. Gastroenterology 125:677–687
Ligresti A, Morera E, Van Der Stelt MM, Monory K, Lutz B, Ortar G, Di Marzo V (2004) Further evidence for the existence of a specific process for the membrane transport of anandamide. Biochem J 380(Pt 1):265–272
Liu J, Batkai S, Pacher P, Harvey-White J, Wagner JA, Cravatt BF, Gao B, Kunos G (2003) Lipopolysaccharide induces anandamide synthesis in macrophages via CD14/MAPK/ phosphoinositide 3-kinase/NF-kappaB independently of platelet-activating factor. J Biol Chem 278:45034–45039
Liu Q, Tonai T, Ueda N (2002) Activation of N-acylethanolamine-releasing phospholipase D by polyamines. Chem Phys Lipids 115:77–84
Lopez-Rodriguez ML, Viso A, Ortega-Gutierrez S, Lastres-Becker I, Gonzalez S, Fernandez-Ruiz JJ, Ramos, JA (2001) Design, synthesis and biological evaluation of novel arachidonic acid derivatives as highly potent and selective endocannabinoid transporter inhibitors. J Med Chem 44:4505–4508
Lopez-Rodriguez ML, Viso A, Ortega-Gutierrez S, Fowler CJ, Tiger G, de Lago E, Fernandez-Ruiz J, Ramos JA (2003a) Design, synthesis and biological evaluation of new endocannabinoid transporter inhibitors. Eur J Med Chem 38:403–412
Lopez-Rodriguez ML, Viso A, Ortega-Gutierrez S, Fowler CJ, Tiger G, de Lago E, Fernandez-Ruiz J, Ramos JA (2003b) Design, synthesis, and biological evaluation of new inhibitors of the endocannabinoid uptake: comparison with effects on fatty acid amidohydrolase. J Med Chem 46:1512–1522
Maccarrone M, Bari M, Lorenzon T, Bisogno T, Di Marzo V, Finazzi-Agrò A (2000a) Anandamide uptake by human endothelial cells and its regulation by nitric oxide. J Biol Chem 275:13484–13492
Maccarrone M, Salvati S, Bari M, Finazzi-Agrò A (2000b) Anandamide and 2-arachidonoylglycerol inhibit fatty acid amide hydrolase by activating the lipoxygenase pathway of the arachidonate cascade. Biochem Biophys Res Commun 278:576–583
Maccarrone M, Valensise H, Bari M, Lazzarin N, Romanini C, Finazzi-Agro’ A (2000c) Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage. Lancet 355:1326–1329
Maccarrone M, De Petrocellis L, Bari M, Fezza F, Salvati S, Di Marzo V, Finazzi-Agrò A (2001) Lipopolysaccharide downregulates fatty acid amide hydrolase expression and increases anandamide levels in human peripheral lymphocytes. Arch Biochem Biophys 393:321–328
Maccarrone M, Bisogno T, Valensise H, Lazzarin N, Fezza F, Manna C, Di Marzo V, Finazzi-Agro’ A (2002a) Low fatty acid amide hydrolase and high anandamide levels are associated with failure to achieve an ongoing pregnancy after IVF and embryo transfer. Mol Hum Reprod 8:188–195
Maccarrone M, Cartoni A, Parolaro D, Margonelli A, Massi P, Bari M, Battista N, Finazzi-Agrò A (2002b) Cannabimimetic activity, binding, and degradation of stearoylethanolamide within the mouse central nervous system. Mol Cell Neurosci 21:126–140
Maccarrone M, Bari M, Di Rienzo M, Finazzi-Agrò A, Rossi A (2003a) Progesterone activates Fatty Acid Amide Hydrolase (FAAH) promoter in Human T lymphocytes through the transcription factor Ikaros: evidence for a synergistic effect of leptin. J Biol Chem 278:32726–32732
Maccarrone M, Di Rienzo M, Finazzi-Agrò A, Rossi A (2003b) Leptin activates the anandamide hydrolase promoter in human T lymphocytes through STAT3. J Biol Chem 278:13318–13324
Maccarrone M, Gubellini P, Bari M, Picconi B, Battista N, Centonze D, Bernardi G, Finazzi-Agro’ A, Calabresi P (2003c) Levodopa treatment reverses endocannabinoid system abnormalities in experimental parkinsonism. J Neurochem 85:1018–1025
Maingret F, Patel AJ, Lazdunski M, Honore E (2001) The endocannabinoid anandamide is a direct and selective blocker of the background K(+) channel TASK-1. EMBO J 20:47–54
Markey SP, Dudding T, Wang TC (2000) Base-and acid-catalyzed interconversions of O-acyland N-acyl-ethanolamines: a cautionary note for lipid analyses. J Lipid Res 41:657–662
Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgansberger W, Di Marzo V, Lutz B (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534
Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutierrez SO, van der Stelt M, Lopez-Rodriguez ML, Casanova E, Schutz G, Zieglgansberger W, Di Marzo V, Behl C, Lutz B (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302:84–88
Martin BR, Beletskaya I, Patrick G, Jefferson R, Winckler R, Deutsch DG, Di Marzo V, Dasse O, Mahadevan A, Razdan RK (2000) Cannabinoid properties of methylfluorophosphonate analogs. J Pharmacol Exp Ther 294:1209–1218
Mascolo N, Izzo AA, Ligresti A, Costagliola A, Pinto L, Cascio MG, Maffia P, Cecio A, Capasso F, Di Marzo V (2002) The endocannabinoid system and the molecular basis of paralytic ileus in mice. FASEB J 16:1973–1975
Matias I, Chen J, De Petrocellis L, Bisogno T, Ligresti A, Fezza F, Krauss AH, Shi L, Protzman CE, Li C, Liang Y, Nieves AL, Kedzie KM, Burk RM, Di Marzo V, Woodward DF (2004) Prostaglandin-ethanolamides (prostamides): in vitro pharmacology and metabolism. J Pharmacol Exp Ther 309:745–757
Maurelli S, Bisogno T, De Petrocellis L, Di Luccia A, Marino G, Di Marzo V (1995) Two novel classes of neuroactive fatty acid amides are substrates for mouse neuroblastoma’ anandamide amidohydrolase’. FEBS Lett 377:82–86
Mazzola C, Micale V, Drago F (2003) Amnesia induced by beta-amyloid fragments is counteracted by cannabinoid CB1 receptor blockade. Eur J Pharmacol 477:219–225
McAllister SD, Glass M (2002) CB(1) and CB(2) receptor-mediated signalling: a focus on endocannabinoids. Prostaglandins Leukot Essent Fatty Acids 66:161–171
McPartland JM (2004) Phylogenomic and chemotaxonomic analysis of the endocannabinoid system. Brain Res Brain Res Rev 45:18–29
McVey DC, Schmid PC, Schmid HH, Vigna, SR (2003) Endocannabinoids induce ileitis in rats via the capsaicin receptor (VR1). J Pharmacol Exp Ther 304:713–722
Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90
Mechoulam R, Fride E, Ben-Shabat S, Meiri U, Horowitz M (1998a) Carbachol, an acetylcholine receptor agonist, enhances production in rat aorta of 2-arachidonoyl glycerol, a hypotensive endocannabinoid. Eur J Pharmacol 362:R1–R3
Mechoulam R, Fride E, Di Marzo V (1998b) Endocannabinoids. Eur J Pharmacol 359:1–18
Monory K, Tzavara ET, Lexime J, Ledent C, Parmentier M, Borsodi A, Hanoune J (2002) Novel, not adenylyl cyclase-coupled cannabinoid binding site in cerebellum of mice. Biochem Biophys Res Commun 292:231–235
Nagan N, Zoeller RA (2001) Plasmalogens: biosynthesis and functions. Prog Lipid Res 40:199–229
Nakane S, Oka S, Arai S, Waku K, Ishima Y, Tokumura A, Sugiura T (2002) 2-Arachidonoylsn-glycero-3-phosphate, an arachidonic acid-containing lysophosphatidic acid: occurrence and rapid enzymatic conversion to 2-arachidonoyl-sn-glycerol, a cannabinoid receptor ligand, in rat brain. Arch Biochem Biophys 402:51–58
Natarajan V, Schmid PC, Reddy PV, Schmid HH (1984) Catabolism of N-acylethanolamine phospholipids by dog brain preparations. J Neurochem 42:1613–1619
Nirodi CS, Crews BC, Kozak KR, Morrow JD, Marnett LJ (2004) The glyceryl ester of prostaglandin E2 mobilizes calcium and activates signal transduction in RAW264.7 cells. Proc Natl Acad Sci USA 101:1840–1845
O’sullivan SE, Kendall DA, Randall MD (2004) Characterisation of the vasorelaxant properties of the novel endocannabinoid N-arachidonoyl-dopamine (NADA). Br J Pharmacol 141:803–812
Offertaler L, Mo FM, Batkai S, Liu J, Begg M, Razdan RK, Martin BR, Bukoski RD, Kunos G (2003) Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor. Mol Pharmacol 63:699–705
Ohno-Shosaku T, Matsui M, Fukudome Y, Shosaku J, Tsubokawa H, Taketo MM, Manabe T, Kano M (2003) Postsynaptic M1 and M3 receptors are responsible for the muscarinic enhancement of retrograde endocannabinoid signalling in the hippocampus. Eur J Neurosci 18:109–116
Oka S, Tsuchie A, Tokumura A, Muramatsu M, Suhara Y, Takayama H, Waku, Sugiura T (2003) Ether-linked analogue of 2-arachidonoylglycerol (noladin ether) was not detected in the brains of various mammalian species. J Neurochem 85:1374–1381
Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N (2004) Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem 279:5298–5305
Ortar G, Ligresti A, De Petrocellis L, Morera E, Di Marzo V (2003) Novel selective and metabolically stable inhibitors of anandamide cellular uptake. Biochem Pharmacol 65:1473–1481
Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R, Shohami E (2001) An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413:527–531
Parmentier-Batteur S, Jin K, Mao XO, Xie L, Greenberg DA (2002) Increased severity of stroke in CB1 cannabinoid receptor knock-out mice. J Neurosci 22:9771–9775
Patricelli MP, Cravatt BF (2000) Clarifying the catalytic roles of conserved residues in the amidase signature family. J Biol Chem 275:19177–19184
Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74:129–180
Pertwee RG (2004) Novel pharmacological targets for cannabinoids. Curr Neuropharmacol 2:9–29
Petersen G, Hansen HS (1999) N-acylphosphatidylethanolamine-hydrolysing phospholipase D lacks the ability to transphosphatidylate. FEBS Lett 455:41–44
Pinto L, Izzo AA, Cascio MG, Bisogno T, Hospodar-Scott K, Brown DR, Mascolo N, Di Marzo V, Capasso F (2002) Endocannabinoids as physiological regulators of colonic propulsion in mice. Gastroenterology 23:227–234
Piomelli D, Beltramo M, Glasnapp S, Lin SY, Goutopoulos A, Xie XQ, Makriyannis A (1999) Structural determinants for recognition and translocation by the anandamide transporter. Proc Natl Acad Sci USA 96:5802–5807
Portella G, Laezza C, Laccetti P, De Petrocellis L, Di Marzo V, Bifulco M (2003) Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth andmetastatic spreading: actions on signals involved in angiogenesis and metastasis. FASEB J 17:1771–1773
Porter AC, Sauer JM, Knierman MD, Becker GW, Berna MJ, Bao J, Nomikos GG, Carter P, Bymaster FP, Leese AB, Felder CC (2002) Characterization of a novel endo cannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther 301:1020–1024
Premkumar LS, Qi ZH, Van Buren J, Raisinghani M (2004) Enhancement of potency and efficacy of NADA by PKC-mediated phosphorylation of vanilloid receptor. J Neurophysiol 91:1442–1449
Price TJ, Patwardhan A, Akopian AN, Hargreaves KM, Flores CM (2004) Modulation of trigeminal sensory neuron activity by the dual cannabinoid-vanilloid agonists anandamide, N-arachidonoyl-dopamine and arachidonyl-2-chloroethylamide. Br J Pharmacol 141:1118–1130
Puffenbarger RA, Kapulin O, Howell JM, Deutsch DG (2001) Characterization of the 5’-sequence of the mouse fatty acid amide hydrolase. Neurosci Lett 314:21–24
Ralevic V, Duncan M, Millns P, Smart D, Wright J, Kendall D (2004) Noladin ether, a putative endocannabinoid, attenuates sensory neurotransmission in the rat isolated mesenteric arterial bed via a non CB1/CB2 Gi/o linked receptor. Br J Pharmacol 142:509–518
Randall MD, Harris D, Kendall DA, Ralevic V (2002) Cardiovascular effects of cannabinoids. Pharmacol Ther 95:191–202
Ravinet Trillou C, Arnone M, Delgorge C, Gonalons N, Keane P, Maffrand JP, Soubrie P (2003) Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol 284:R345–R353
Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrie P (2004) CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord 28:640–648
Ronesi J, Gerdeman GL, Lovinger DM (2004) Disruption of endocannabinoid release and striatal long-term depression by postsynaptic blockade of endocannabinoid membrane transport. J Neurosci 24:1673–1679
Ross RA (2003) Anandamide and vanilloid TRPV1 receptors. Br J Pharmacol 140:790–801
Ross RA, Gibson TM, Brockie HC, Leslie M, Pashmi G, Craib SJ, Di Marzo V, Pertwee RG (2001) Structure-activity relationship for the endogenous cannabinoid, anandamide, and certain of its analogues at vanilloid receptors in transfected cells and vas deferens. Br J Pharmacol 132:631–640
Ruiz-Llorente L, Ortega-Gutiérrez S, Viso A, Sánchez MG, Sánchez AM, Fernández C, Ramos JA, Hillard C, Lasunción MA, López-Rodríguez ML, Díaz-Laviada I (2004) Characterization of an anandamide degradation system in prostate epithelial PC-3 cells: synthesis of new transporter inhibitors as tools for this study. Br J Pharmacol 141:457–467
Sagan S, Venance L, Torrens Y, Cordier J, Glowinski J, Giaume C (1999) Anandamide and WIN 55212-2 inhibit cyclic AMP formation through G-protein-coupled receptors distinct from CB1 cannabinoid receptors in cultured astrocytes. Eur J Neurosci 11:691–699
Sanchez C, de Ceballos ML, del Pulgar TG, Rueda D, Corbacho C, Velasco G, Galve-Roperh I, Huffman JW, Ramon y Cajal S, Guzman M (2001) Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res 61:5784–5789
Schmid HH, Schmid PC, Natarajan V (1990) N-acylated glycerophospholipids and their derivatives. Prog Lipid Res 29:1–43
Schmid HH, Schmid PC, Natarajan V (1996) The N-acylation-phosphodiesterase pathway and cell signalling. Chem Phys Lipids 80:133–142
Schmid HH, Schmid PC, Berdyshev EV (2002a) Cell signaling by endocannabinoids and their congeners: questions of selectivity and other challenges. Chem Phys Lipids 121:111–134
Schmid PC, Wold LE, Krebsbach RJ, Berdyshev EV, Schmid HH (2002b) Anandamide and other N-acylethanolamines in human tumors. Lipids 37:907–912
Silverdale MA, McGuire S, McInnes A, Crossman AR, Brotchie JM (2001) Striatal cannabinoid CB1 receptor mRNA expression is decreased in the reserpine-treated rat model of Parkinson’s disease. Exp Neurol 169:400–406
Smart D, Gunthorpe MJ, Jerman JC, Nasir S, Gray J, Muir AI, Chambers JK, Randall AD, Davis JB (2000) The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br J Pharmacol 129:227–230
Stella N, Piomelli D (2001) Receptor-dependent formation of endogenous cannabinoids in cortical neurons. Eur J Pharmacol 425:189–196
Stella N, Schweitzer P, Piomelli D (1997) A second endogenous cannabinoid that modulates long-term potentiation. Nature 388:773–778
Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97
Sugiura T, Kondo S, Sukagawa A, Tonegawa T, Nakane S, Yamashita A, Waku K (1996a) Enzymatic synthesis of anandamide, an endogenous cannabinoid receptor ligand, through N-acylphosphatidylethanolamine pathway in testis: involvement of Ca(2+)-dependent transacylase and phosphodiesterase activities. Biochem Biophys Res Commun 218:113–117
Sugiura T, Kondo S, Sukagawa A, Tonegawa T, Nakane S, Yamashita A, Ishima Y, Waku K (1996b) Transacylase-mediated and phosphodiesterase-mediated synthesis of Narachidonoylethanolamine, an endogenous cannabinoid-receptor ligand, in rat brain microsomes. Comparison with synthesis from free arachidonic acid and ethanolamine. Eur J Biochem 240:53–62
Sugiura T, Kodaka T, Nakane S, Kishimoto S, Kondo S, Waku K (1998) Detection of an endogenous cannabimimetic molecule, 2-arachidonoylglycerol, and cannabinoid CB1 receptor mRNA in human vascular cells: is 2-arachidonoylglycerol a possible vasomodulator? Biochem Biophys Res Commun 243:838–843
Sugiura T, Kodaka T, Nakane S, Miyashita T, Kondo S, Suhara Y, Takayama H, Waku K, Seki C, Baba N, Ishima Y (1999) Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor. Structure-activity relationship of 2-arachidonoylglycerol, ether-linked analogues, and related compounds. J Biol Chem 274:2794–2801
Sugiura T, Yoshinaga N, Waku K (2001) Rapid generation of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, in rat brain after decapitation. Neurosci Lett 297:175–178
Sugiura T, Kobayashi Y, Oka S, Waku, K (2002) Biosynthesis and degradation of anandamide and 2-arachidonoylglycerol and their possible physiological significance. Prostaglandins Leukot Essent Fatty Acids 66:173–192
Sun YX, Tsuboi K, Okamoto Y, Tonai T, Murakami M, Kudo I, Ueda N (2004) Biosynthesis of anandamide and N-palmitoylethanolamine by sequential actions of phospholipase A2 and lysophospholipase D. Biochem J 380:749–756
Szallasi A, Blumberg PM (1999) Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol Rev 51:159–212
Tarzia G, Duranti A, Tontini A, Piersanti G, Mor M, Rivara S, Plazzi PV, Park C, Kathuria S, Piomelli D (2003) Design, synthesis, and structure-activity relationships of alkylcarbamic acid aryl esters, a new class of fatty acid amide hydrolase inhibitors. J Med Chem 46:2352–2360
Ueda N (2002) Endocannabinoid hydrolases. Prostaglandins Other Lipid Mediat 68-69:521–534
Ueda N, Yamamoto K, Yamamoto S, Tokunaga T, Shirakawa E, Shinkai H, Ogawa M, Sato T, Kudo I, Inoue K (1995) Lipoxygenase-catalyzed oxygenation of arachidonylethanolamide, a cannabinoid receptor agonist. Biochim Biophys Acta 1254:127–134
Ueda N, Liu Q, Yamanaka K (2001a) Marked activation of the N-acylphosphatidylethanolamine-hydrolyzing phosphodiesterase by divalent cations. Biochim Biophys Acta 1532:121–127
Ueda N, Yamanaka K, Yamamoto S (2001b) Purification and characterization of an acid amidase selective for N-palmitoylethanolamine, a putative endogenous anti-inflammatory substance. J Biol Chem 276:35552–35557
van der Stelt M, Di Marzo V (2004) Endovanilloids: endogenous ligands of transient receptor potential vanilloid 1 (TRPV1) channels. Eur J Pharmacol 271:1827–1834
van der Stelt M, Veldhuis WB, van Haaften GW, Fezza F, Bisogno T, Bar PR, Veldink GA, Vliegenthart JF, Di Marzo V, Nicolay K (2001) Exogenous anandamide protects rat brain against acute neuronal injury in vivo. J Neurosci 21:8765–8771
van der Stelt M, van Kuik JA, Bari M, van Zadelhoff G, Leeflang BR, Veldink GA, Finazzi-Agrò A, Vliegenthart JF, Maccarrone M (2002) Oxygenated metabolites of anandamide and 2-arachidonoylglycerol: conformational analysis and interaction with cannabinoid receptors, membrane transporter, and fatty acid amide hydrolase. J Med Chem 45:3709–3720
van der Stelt M, Hansen HH, Veldhuis WB, Bar PR, Nicolay K, Veldink GA, Vliegenthart JF, Hansen HS (2003) Biosynthesis of endocannabinoids and their modes of action in neurodegenerative diseases. Neurotox Res 5:183–200
Varga K, Wagner JA, Bridgen DT, Kunos G (1998) Platelet-and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension. FASEB J 12:1035–1044
Veldhuis WB, van der Stelt M, Wadman MW, van Zadelhoff G, Maccarrone M, Fezza F, Veldink GA, Vliegenthart JF, Bar PR, Nicolay K, Di Marzo V (2003) Neuroprotection by the endogenous cannabinoid anandamide and arvanil against in vivo excitotoxicity in the rat: role of vanilloid receptors and lipoxygenases. J Neurosci 23:4127–4133
Venance L, Piomelli D, Glowinski J, Giaume C (1995) Inhibition by anandamide of gap junctions and intercellular calcium signalling in striatal astrocytes. Nature 376:590–594
Wagner JA, Varga K, Ellis EF, Rzigalinski BA, Martin BR, Kunos G (1997) Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock. Nature 390:518–521
Wagner JA, Varga K, Jarai Z, Kunos G (1999) Mesenteric vasodilation-mediated by endothelial anandamide receptors. Hypertension 33:429–434
Wagner JA, Hu K, Bauersachs J, Karcher J, Wiesler M, Goparaju SK, Kunos G, Ertl G (2001) Endogenous cannabinoids mediate hypotension after experimental myocardial infarction. J Am Coll Cardiol 38:2048–2054
Waleh NS, Cravatt BF, Apte-Deshpande A, Terao A, Kilduff TS (2002) Transcriptional regulation of the mouse fatty acid amide hydrolase gene. Gene 291:203–210
Walker JM, Huang SM, Strangman NM, Tsou K, Sanudo-Pena MC (1999) Pain modulation by release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci USA 96:12198–12203
Walter L, Stella N (2003) Endothelin-1 increases 2-arachidonoyl glycerol (2-AG) production in astrocytes. Glia 44:85–90
Walter L, Stella N (2004) Cannabinoids and neuroinflammation. Br J Pharmacol 141:775–785
Walter L, Franklin A, Witting A, Wade C, Xie Y, Kunos G, Mackie K, Stella N (2003) Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci 23:1398–1405
Wang H, Matsumoto H, Guo Y, Paria BC, Roberts RL, Dey SK (2003) Differential G protein-coupled cannabinoid receptor signaling by anandamide directs blastocyst activation for implantation. Proc Natl Acad Sci USA 100:14914–14919
Watanabe H, Vriens J, Prenen J, Droogmans G, Voets T, Nilius B (2003) Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature 424:434–438
Wiley JL, Martin BR (2003) Cannabinoid pharmacological properties common to other centrally acting drugs. Eur J Pharmacol 471:185–193
Williams EJ, Walsh FS, Doherty P (2003) The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response. J Cell Biol 160:481–486
Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296:678–682
Yu M, Ives D, Ramesha CS (1997) Synthesis of prostaglandin E2 ethanolamide from anandamide by cyclooxygenase-2. J Biol Chem 272:21181–21186
Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D, Hogestatt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamid. Nature 400:452–457
Zygmunt PM, Chuang H, Movahed P, Julius D, Hogestatt ED (2000) The anandamide transport inhibitor AM404 activates vanilloid receptors. Eur J Pharmacol 396:39–42
Zygmunt PM, Andersson DA, Hogestatt ED (2002) Delta 9-tetrahydrocannabinol and cannabinol activate capsaicin-sensitive sensory nerves via a CB1 and CB2 cannabinoid receptor-independent mechanism. J Neurosci 22:4720–4727
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2005 Springer-Verlag
About this chapter
Cite this chapter
Di Marzo, V., Bisogno, T., De Petrocellis, L. (2005). The Biosynthesis, Fate and Pharmacological Properties of Endocannabinoids. In: Pertwee, R.G. (eds) Cannabinoids. Handbook of Experimental Pharmacology, vol 168. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-26573-2_5
Download citation
DOI: https://doi.org/10.1007/3-540-26573-2_5
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-22565-2
Online ISBN: 978-3-540-26573-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)