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Cannabinoids pp 147-185 | Cite as

The Biosynthesis, Fate and Pharmacological Properties of Endocannabinoids

  • V. Di Marzo
  • T. Bisogno
  • L. De Petrocellis
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 168)

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.

Keywords

Anandamide 2-Arachidonoylglycerol Cannabinoid Enzyme Inhibitors 

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References

  1. 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 284:1209–1217PubMedGoogle Scholar
  2. 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 17:2611–2618PubMedCrossRefGoogle Scholar
  3. 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 84:585–591PubMedCrossRefGoogle Scholar
  4. Andersson DA, Adner M, Hogestatt ED, Zygmunt PM (2002) Mechanisms underlying tissue selectivity of anandamide and other vanilloid receptor agonists. Mol Pharmacol 62:705–713PubMedCrossRefGoogle Scholar
  5. 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 13:43–46PubMedCrossRefGoogle Scholar
  6. 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 404:84–87PubMedCrossRefGoogle Scholar
  7. 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 15:300–302PubMedGoogle Scholar
  8. 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 1535:78–86PubMedGoogle Scholar
  9. 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 466:73–83PubMedCrossRefGoogle Scholar
  10. 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 7:827–832PubMedGoogle Scholar
  11. Beltramo M, Piomelli D (2000) Carrier-mediated transport and enzymatic hydrolysis of the endogenous cannabinoid 2-arachidonylglycerol. Neuroreport 11:1231–1235PubMedGoogle Scholar
  12. 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 277:1094–1097PubMedCrossRefGoogle Scholar
  13. 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 353:23–31PubMedCrossRefGoogle Scholar
  14. 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 63:908–914PubMedCrossRefGoogle Scholar
  15. 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 15:2171–2178PubMedCrossRefGoogle Scholar
  16. 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 469:527–533PubMedGoogle Scholar
  17. 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 33:181–191PubMedCrossRefGoogle Scholar
  18. 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 41:195–202PubMedCrossRefGoogle Scholar
  19. 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 15:2745–2747PubMedGoogle Scholar
  20. 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 272:3315–3323PubMedGoogle Scholar
  21. 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 322:671–677PubMedGoogle Scholar
  22. 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 248:515–522PubMedCrossRefGoogle Scholar
  23. 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 256:377–380PubMedCrossRefGoogle Scholar
  24. 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 72:2113–2119PubMedCrossRefGoogle Scholar
  25. 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 351:817–824PubMedCrossRefGoogle Scholar
  26. 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 268:1982–1989PubMedCrossRefGoogle Scholar
  27. 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 8:533–547PubMedCrossRefGoogle Scholar
  28. 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 163:463–468PubMedCrossRefGoogle Scholar
  29. 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 97:5044–5049PubMedCrossRefGoogle Scholar
  30. 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 11:1517–1520PubMedGoogle Scholar
  31. 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 197:740–746PubMedCrossRefGoogle Scholar
  32. Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF (2002) Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science 298:1793–1796PubMedCrossRefGoogle Scholar
  33. Breivogel CS, Griffin G, Di Marzo V, Martin BR (2001) Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol Pharmacol 60:155–163PubMedGoogle Scholar
  34. Brenowitz SD, Regehr WG (2003) Calcium dependence of retrograde inhibition by endocannabinoids at synapses onto Purkinje cells. J Neurosci 23:6373–6384PubMedGoogle Scholar
  35. 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 439:83–92PubMedCrossRefGoogle Scholar
  36. Cadas H, di Tomaso E, Piomelli D (1997) Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J Neurosci 17:1226–1242PubMedGoogle Scholar
  37. Calignano A, La Rana G, Giuffrida A, Piomelli D (1998) Control of pain initiation by endogenous cannabinoids. Nature 394:277–281PubMedGoogle Scholar
  38. 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 65:999–1007PubMedCrossRefGoogle Scholar
  39. 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 111:43–50PubMedCrossRefGoogle Scholar
  40. 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 20:7033–7040PubMedCrossRefGoogle Scholar
  41. Chevaleyre V, Castillo PE (2003) Heterosynaptic LTD of hippocampal GABAergic synapses: a novel role of endocannabinoids in regulating excitability. Neuron 38:461–472PubMedGoogle Scholar
  42. 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 23:3916–3923PubMedGoogle Scholar
  43. 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 112:423–431PubMedCrossRefGoogle Scholar
  44. 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 134:30–37PubMedCrossRefGoogle Scholar
  45. Cravatt BF, Lichtman AH (2003) Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system. Curr Opin Chem Biol 7:469–475PubMedCrossRefGoogle Scholar
  46. 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 384:83–87PubMedCrossRefGoogle Scholar
  47. 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 98:9371–9376PubMedCrossRefGoogle Scholar
  48. 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 449:99–103PubMedGoogle Scholar
  49. 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 1007:152–159PubMedGoogle Scholar
  50. 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 484:249–257PubMedGoogle Scholar
  51. 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 231:82–88PubMedGoogle Scholar
  52. 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 483:52–56PubMedGoogle Scholar
  53. 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 276:12856–12863PubMedGoogle Scholar
  54. 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 98:705–713PubMedCrossRefGoogle Scholar
  55. 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 231:217–221PubMedCrossRefGoogle Scholar
  56. 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 53:255–260PubMedCrossRefGoogle Scholar
  57. 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 276:6967–6973PubMedCrossRefGoogle Scholar
  58. Deutsch DG, Ueda N, Yamamoto S (2002) The fatty acid amide hydrolase (FAAH). Prostaglandins Leukot Essent Fatty Acids 66:201–210PubMedCrossRefGoogle Scholar
  59. 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 258:1946–1949PubMedGoogle Scholar
  60. Di Marzo V, Fontana A (1995) Anandamide, an endogenous cannabinomimetic eicosanoid:’ killing two birds with one stone’. Prostaglandins Leukot Essent Fatty Acids 53:1–11PubMedGoogle Scholar
  61. 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 372:686–691PubMedGoogle Scholar
  62. 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 316:977–984PubMedGoogle Scholar
  63. 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 227:281–288PubMedGoogle Scholar
  64. 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 331:15–19PubMedGoogle Scholar
  65. Di Marzo V, Melck D, Bisogno T, De Petrocellis L (1998b) Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci 21:521–528PubMedGoogle Scholar
  66. 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 264:258–267PubMedGoogle Scholar
  67. 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 34:319–325Google Scholar
  68. 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 75:2434–2444PubMedGoogle Scholar
  69. 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 14:1432–1438PubMedGoogle Scholar
  70. Di Marzo V, Bisogno T, De Petrocellis L (2001a) Anandamide: some like it hot. Trends Pharmacol Sci 22:346–349PubMedGoogle Scholar
  71. 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 281:444–451PubMedGoogle Scholar
  72. 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 410:822–825PubMedGoogle Scholar
  73. 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 420:123–131PubMedGoogle Scholar
  74. Di Marzo V, Blumberg PM, Szallasi A (2002a) Endovanilloid signaling in pain. Curr Opin Neurobiol 12:372–379PubMedGoogle Scholar
  75. Di Marzo V, De Petrocellis L, Fezza F, Ligresti A, Bisogno T (2002b) Anandamide receptors. Prostaglandins Leukot Essent Fatty Acids 66:377–391PubMedGoogle Scholar
  76. 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 300:984–991PubMedGoogle Scholar
  77. Di Marzo V, Bifulco M, De Petrocellis L (2004) The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 3:771–784PubMedCrossRefGoogle Scholar
  78. 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 99:10819–10824PubMedCrossRefGoogle Scholar
  79. 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 54:180–188PubMedGoogle Scholar
  80. 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 265:2081–2085CrossRefGoogle Scholar
  81. Evans RM, Scott RH, Ross RA (2004) Multiple actions of anandamide on neonatal rat cultured sensory neurones. Br J Pharmacol 141:1223–1233PubMedCrossRefGoogle Scholar
  82. 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 513:294–298PubMedCrossRefGoogle Scholar
  83. 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 18:225–231PubMedGoogle Scholar
  84. 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 492:1–11PubMedCrossRefGoogle Scholar
  85. 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 23:7767–7775PubMedGoogle Scholar
  86. 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 6:313–319PubMedGoogle Scholar
  87. 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 100:4269–4274PubMedCrossRefGoogle Scholar
  88. Goparaju SK, Ueda N, Taniguchi K, Yamamoto S (1999) Enzymes of porcine brain hydrolyzing 2-arachidonoylglycerol, an endogenous ligand of cannabinoid receptors. Biochem Pharmacol 57:417–423PubMedCrossRefGoogle Scholar
  89. 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 65:665–674PubMedCrossRefGoogle Scholar
  90. Hajos N, Freund TF (2002) Pharmacological separation of cannabinoid sensitive receptors on hippocampal excitatory and inhibitory fibers. Neuropharmacology 43:503–510PubMedGoogle Scholar
  91. Hajos N, Ledent C, Freund TF (2001) Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience 106:1–4PubMedGoogle Scholar
  92. Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (-)delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95:8268–8273PubMedCrossRefGoogle Scholar
  93. 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 55:719–725PubMedCrossRefGoogle Scholar
  94. 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 98:3662–3665PubMedCrossRefGoogle Scholar
  95. Hiley CR, Ford WR (2004) Cannabinoid pharmacology in the cardiovascular system: potential protective mechanisms through lipid signalling. Biol Rev Camb Philos Soc 79:187–205PubMedGoogle Scholar
  96. Hillard CJ, Jarrahian A (2000) The movement of N-arachidonoylethanolamine (anandamide) across cellular membranes. Chem Phys Lipids 108:123–134PubMedGoogle Scholar
  97. Hillard CJ, Jarrahian A (2003) Cellular accumulation of anandamide: consensus and controversy. Br J Pharmacol 140:802–808PubMedCrossRefGoogle Scholar
  98. Hillard CJ, Edgemond WS, Jarrahian A, Campbell WB (1997) Accumulation of N-arachidonoylethanolamine (anandamide) into cerebellar granule cells occurs via facilitated diffusion. J Neurochem 69:631–638PubMedGoogle Scholar
  99. Ho SY, Delgado L, Storch J (2002) Monoacylglycerol metabolism in human intestinal Caco-2 cells: evidence for metabolic compartmentation and hydrolysis. J Biol Chem 277:1816–1823PubMedGoogle Scholar
  100. Horrocks LA (1989) Sources for brain arachidonic acid uptake and turnover in glycerophospholipids. Ann N Y Acad Sci 559:17–24PubMedGoogle Scholar
  101. 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 276:42639–42644PubMedGoogle Scholar
  102. 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 99:8400–8405PubMedGoogle Scholar
  103. 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 97:6155–6160PubMedGoogle Scholar
  104. 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 134:563–570PubMedCrossRefGoogle Scholar
  105. 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 125:765–774PubMedCrossRefGoogle Scholar
  106. 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 96:14136–14141PubMedCrossRefGoogle Scholar
  107. 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 35:679–684PubMedGoogle Scholar
  108. 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 74:2597–2606PubMedCrossRefGoogle Scholar
  109. Jordt SE, Julius D (2002) Molecularbasis for species-specific sensitivity to “hot” chilipeppers. Cell 108:421–430PubMedCrossRefGoogle Scholar
  110. 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 427:260–265PubMedCrossRefGoogle Scholar
  111. 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 272:27218–27223PubMedGoogle Scholar
  112. 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 272:11–18PubMedCrossRefGoogle Scholar
  113. 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 9:76–81PubMedCrossRefGoogle Scholar
  114. 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 22:10182–10191PubMedGoogle Scholar
  115. 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 136:550–557PubMedCrossRefGoogle Scholar
  116. 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 429:152–156PubMedCrossRefGoogle Scholar
  117. Koutek B, Prestwich GD, Howlett AC, Chin SA, Salehani D, Akhavan N, Deutsch DG (1994) Inhibitors of arachidonoyl ethanolamide hydrolysis. J Biol Chem 269:22937–22940PubMedGoogle Scholar
  118. Kozak KR, Marnett LJ (2002) Oxidative metabolism of endocannabinoids. Prostaglandins Leukot Essent Fatty Acids 66:211–220PubMedCrossRefGoogle Scholar
  119. 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 276:36993–36998PubMedGoogle Scholar
  120. 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 277:23278–23286PubMedGoogle Scholar
  121. Lambert DM, Vandevoorde S, Jonsson KO, Fowler CJ (2002) The palmitoylethanolamide family: a new class of anti-inflammatory agents? Curr Med Chem 9:663–674PubMedGoogle Scholar
  122. 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 12:2125–2129PubMedGoogle Scholar
  123. 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 302:73–79PubMedCrossRefGoogle Scholar
  124. 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 125:677–687PubMedCrossRefGoogle Scholar
  125. 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):265–272PubMedGoogle Scholar
  126. 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 278:45034–45039PubMedGoogle Scholar
  127. Liu Q, Tonai T, Ueda N (2002) Activation of N-acylethanolamine-releasing phospholipase D by polyamines. Chem Phys Lipids 115:77–84PubMedGoogle Scholar
  128. 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 44:4505–4508PubMedGoogle Scholar
  129. 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 38:403–412PubMedGoogle Scholar
  130. 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 46:1512–1522PubMedGoogle Scholar
  131. 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 275:13484–13492PubMedGoogle Scholar
  132. 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 278:576–583PubMedCrossRefGoogle Scholar
  133. 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 355:1326–1329PubMedCrossRefGoogle Scholar
  134. 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 393:321–328PubMedCrossRefGoogle Scholar
  135. 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 8:188–195PubMedCrossRefGoogle Scholar
  136. 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 21:126–140PubMedCrossRefGoogle Scholar
  137. 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 278:32726–32732PubMedGoogle Scholar
  138. 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 278:13318–13324PubMedGoogle Scholar
  139. 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 85:1018–1025PubMedCrossRefGoogle Scholar
  140. 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 20:47–54PubMedCrossRefGoogle Scholar
  141. 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 41:657–662PubMedGoogle Scholar
  142. 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 418:530–534PubMedCrossRefGoogle Scholar
  143. 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 302:84–88PubMedCrossRefGoogle Scholar
  144. 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 294:1209–1218PubMedGoogle Scholar
  145. 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 16:1973–1975PubMedGoogle Scholar
  146. 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 309:745–757PubMedCrossRefGoogle Scholar
  147. 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 377:82–86PubMedCrossRefGoogle Scholar
  148. Mazzola C, Micale V, Drago F (2003) Amnesia induced by beta-amyloid fragments is counteracted by cannabinoid CB1 receptor blockade. Eur J Pharmacol 477:219–225PubMedCrossRefGoogle Scholar
  149. McAllister SD, Glass M (2002) CB(1) and CB(2) receptor-mediated signalling: a focus on endocannabinoids. Prostaglandins Leukot Essent Fatty Acids 66:161–171PubMedCrossRefGoogle Scholar
  150. McPartland JM (2004) Phylogenomic and chemotaxonomic analysis of the endocannabinoid system. Brain Res Brain Res Rev 45:18–29PubMedCrossRefGoogle Scholar
  151. McVey DC, Schmid PC, Schmid HH, Vigna, SR (2003) Endocannabinoids induce ileitis in rats via the capsaicin receptor (VR1). J Pharmacol Exp Ther 304:713–722PubMedCrossRefGoogle Scholar
  152. 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 50:83–90PubMedCrossRefGoogle Scholar
  153. 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–R3PubMedCrossRefGoogle Scholar
  154. Mechoulam R, Fride E, Di Marzo V (1998b) Endocannabinoids. Eur J Pharmacol 359:1–18PubMedCrossRefGoogle Scholar
  155. 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 292:231–235PubMedCrossRefGoogle Scholar
  156. Nagan N, Zoeller RA (2001) Plasmalogens: biosynthesis and functions. Prog Lipid Res 40:199–229PubMedGoogle Scholar
  157. 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 402:51–58PubMedCrossRefGoogle Scholar
  158. Natarajan V, Schmid PC, Reddy PV, Schmid HH (1984) Catabolism of N-acylethanolamine phospholipids by dog brain preparations. J Neurochem 42:1613–1619PubMedGoogle Scholar
  159. 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 101:1840–1845PubMedCrossRefGoogle Scholar
  160. O’sullivan SE, Kendall DA, Randall MD (2004) Characterisation of the vasorelaxant properties of the novel endocannabinoid N-arachidonoyl-dopamine (NADA). Br J Pharmacol 141:803–812PubMedGoogle Scholar
  161. 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 63:699–705PubMedCrossRefGoogle Scholar
  162. 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 18:109–116PubMedCrossRefGoogle Scholar
  163. 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 85:1374–1381PubMedCrossRefGoogle Scholar
  164. 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 279:5298–5305PubMedCrossRefGoogle Scholar
  165. 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 65:1473–1481PubMedCrossRefGoogle Scholar
  166. 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 413:527–531PubMedCrossRefGoogle Scholar
  167. 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 22:9771–9775PubMedGoogle Scholar
  168. Patricelli MP, Cravatt BF (2000) Clarifying the catalytic roles of conserved residues in the amidase signature family. J Biol Chem 275:19177–19184PubMedCrossRefGoogle Scholar
  169. Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74:129–180PubMedCrossRefGoogle Scholar
  170. Pertwee RG (2004) Novel pharmacological targets for cannabinoids. Curr Neuropharmacol 2:9–29Google Scholar
  171. Petersen G, Hansen HS (1999) N-acylphosphatidylethanolamine-hydrolysing phospholipase D lacks the ability to transphosphatidylate. FEBS Lett 455:41–44PubMedCrossRefGoogle Scholar
  172. 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 23:227–234Google Scholar
  173. 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 96:5802–5807PubMedCrossRefGoogle Scholar
  174. 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 17:1771–1773PubMedGoogle Scholar
  175. 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 301:1020–1024PubMedCrossRefGoogle Scholar
  176. 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 91:1442–1449PubMedGoogle Scholar
  177. 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 141:1118–1130PubMedCrossRefGoogle Scholar
  178. Puffenbarger RA, Kapulin O, Howell JM, Deutsch DG (2001) Characterization of the 5’-sequence of the mouse fatty acid amide hydrolase. Neurosci Lett 314:21–24PubMedCrossRefGoogle Scholar
  179. 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 142:509–518PubMedGoogle Scholar
  180. Randall MD, Harris D, Kendall DA, Ralevic V (2002) Cardiovascular effects of cannabinoids. Pharmacol Ther 95:191–202PubMedCrossRefGoogle Scholar
  181. 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–R353PubMedGoogle Scholar
  182. 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 28:640–648PubMedCrossRefGoogle Scholar
  183. 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 24:1673–1679PubMedCrossRefGoogle Scholar
  184. Ross RA (2003) Anandamide and vanilloid TRPV1 receptors. Br J Pharmacol 140:790–801PubMedCrossRefGoogle Scholar
  185. 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 132:631–640PubMedCrossRefGoogle Scholar
  186. 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 141:457–467PubMedCrossRefGoogle Scholar
  187. 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 11:691–699PubMedCrossRefGoogle Scholar
  188. 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 61:5784–5789PubMedGoogle Scholar
  189. Schmid HH, Schmid PC, Natarajan V (1990) N-acylated glycerophospholipids and their derivatives. Prog Lipid Res 29:1–43PubMedCrossRefGoogle Scholar
  190. Schmid HH, Schmid PC, Natarajan V (1996) The N-acylation-phosphodiesterase pathway and cell signalling. Chem Phys Lipids 80:133–142PubMedCrossRefGoogle Scholar
  191. Schmid HH, Schmid PC, Berdyshev EV (2002a) Cell signaling by endocannabinoids and their congeners: questions of selectivity and other challenges. Chem Phys Lipids 121:111–134PubMedGoogle Scholar
  192. Schmid PC, Wold LE, Krebsbach RJ, Berdyshev EV, Schmid HH (2002b) Anandamide and other N-acylethanolamines in human tumors. Lipids 37:907–912PubMedGoogle Scholar
  193. 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 169:400–406PubMedCrossRefGoogle Scholar
  194. 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 129:227–230PubMedGoogle Scholar
  195. Stella N, Piomelli D (2001) Receptor-dependent formation of endogenous cannabinoids in cortical neurons. Eur J Pharmacol 425:189–196PubMedCrossRefGoogle Scholar
  196. Stella N, Schweitzer P, Piomelli D (1997) A second endogenous cannabinoid that modulates long-term potentiation. Nature 388:773–778PubMedGoogle Scholar
  197. 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 215:89–97PubMedCrossRefGoogle Scholar
  198. 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 218:113–117PubMedCrossRefGoogle Scholar
  199. 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 240:53–62PubMedCrossRefGoogle Scholar
  200. 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 243:838–843PubMedCrossRefGoogle Scholar
  201. 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 274:2794–2801PubMedCrossRefGoogle Scholar
  202. Sugiura T, Yoshinaga N, Waku K (2001) Rapid generation of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, in rat brain after decapitation. Neurosci Lett 297:175–178PubMedCrossRefGoogle Scholar
  203. 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 66:173–192PubMedCrossRefGoogle Scholar
  204. 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 380:749–756PubMedCrossRefGoogle Scholar
  205. Szallasi A, Blumberg PM (1999) Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol Rev 51:159–212PubMedGoogle Scholar
  206. 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 46:2352–2360PubMedCrossRefGoogle Scholar
  207. Ueda N (2002) Endocannabinoid hydrolases. Prostaglandins Other Lipid Mediat 68-69:521–534PubMedGoogle Scholar
  208. 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 1254:127–134PubMedGoogle Scholar
  209. Ueda N, Liu Q, Yamanaka K (2001a) Marked activation of the N-acylphosphatidylethanolamine-hydrolyzing phosphodiesterase by divalent cations. Biochim Biophys Acta 1532:121–127PubMedGoogle Scholar
  210. 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 276:35552–35557PubMedGoogle Scholar
  211. van der Stelt M, Di Marzo V (2004) Endovanilloids: endogenous ligands of transient receptor potential vanilloid 1 (TRPV1) channels. Eur J Pharmacol 271:1827–1834Google Scholar
  212. 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 21:8765–8771PubMedGoogle Scholar
  213. 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 45:3709–3720PubMedGoogle Scholar
  214. 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 5:183–200PubMedGoogle Scholar
  215. Varga K, Wagner JA, Bridgen DT, Kunos G (1998) Platelet-and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension. FASEB J 12:1035–1044PubMedGoogle Scholar
  216. 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 23:4127–4133PubMedGoogle Scholar
  217. Venance L, Piomelli D, Glowinski J, Giaume C (1995) Inhibition by anandamide of gap junctions and intercellular calcium signalling in striatal astrocytes. Nature 376:590–594PubMedCrossRefGoogle Scholar
  218. Wagner JA, Varga K, Ellis EF, Rzigalinski BA, Martin BR, Kunos G (1997) Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock. Nature 390:518–521PubMedGoogle Scholar
  219. Wagner JA, Varga K, Jarai Z, Kunos G (1999) Mesenteric vasodilation-mediated by endothelial anandamide receptors. Hypertension 33:429–434PubMedGoogle Scholar
  220. 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 38:2048–2054PubMedCrossRefGoogle Scholar
  221. Waleh NS, Cravatt BF, Apte-Deshpande A, Terao A, Kilduff TS (2002) Transcriptional regulation of the mouse fatty acid amide hydrolase gene. Gene 291:203–210PubMedCrossRefGoogle Scholar
  222. 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 96:12198–12203PubMedGoogle Scholar
  223. Walter L, Stella N (2003) Endothelin-1 increases 2-arachidonoyl glycerol (2-AG) production in astrocytes. Glia 44:85–90PubMedCrossRefGoogle Scholar
  224. Walter L, Stella N (2004) Cannabinoids and neuroinflammation. Br J Pharmacol 141:775–785PubMedCrossRefGoogle Scholar
  225. 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 23:1398–1405PubMedGoogle Scholar
  226. 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 100:14914–14919PubMedGoogle Scholar
  227. 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 424:434–438PubMedGoogle Scholar
  228. Wiley JL, Martin BR (2003) Cannabinoid pharmacological properties common to other centrally acting drugs. Eur J Pharmacol 471:185–193PubMedCrossRefGoogle Scholar
  229. 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 160:481–486PubMedCrossRefGoogle Scholar
  230. Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296:678–682PubMedCrossRefGoogle Scholar
  231. Yu M, Ives D, Ramesha CS (1997) Synthesis of prostaglandin E2 ethanolamide from anandamide by cyclooxygenase-2. J Biol Chem 272:21181–21186PubMedGoogle Scholar
  232. 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 400:452–457PubMedGoogle Scholar
  233. Zygmunt PM, Chuang H, Movahed P, Julius D, Hogestatt ED (2000) The anandamide transport inhibitor AM404 activates vanilloid receptors. Eur J Pharmacol 396:39–42PubMedCrossRefGoogle Scholar
  234. 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 22:4720–4727PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • V. Di Marzo
    • 1
  • T. Bisogno
    • 1
  • L. De Petrocellis
    • 2
  1. 1.Endocannabinoid Research GroupIstituto di Chimica BiomolecolarePozzuoli (Napoli)Italy
  2. 2.Endocannabinoid Research GroupIstituto di Cibernetica, Consiglio Nazionale delle RicercheItaly

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