Biosynthesis and Fate of Endocannabinoids

  • Maria Grazia CascioEmail author
  • Pietro Marini
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 231)


Since the discovery of the two cannabinoid receptors, CB1 and CB2, several molecules, commonly defined as endocannabinoids, able to bind to and functionally activate these receptors, have been discovered and characterized. Although the general thought was that the endocannabinoids were mainly derivatives of the n-6 fatty acid arachidonic acid, recent data have shown that also derivatives (ethanolamides) of n-3 fatty acids may be classified as endocannabinoids. Whether the n-3 endocannabinoids follow the same biosynthetic and metabolic routes of the n-6 endocannabinoids is not yet clear and so warrants further investigation. In this review, we describe the primary biosynthetic and metabolic pathways for the two well-established endocannabinoids, anandamide and 2-arachidonoylglycerol.


2-arachidonoylglycerol Anandamide Biosynthesis Degradation Endocannabinoids Uptake 





2-Arachidonoylglyceryl ether


Arachidonic acid


Alpha/beta hydrolase 4


Alpha/beta hydrolase domain




Aspartic acid










Diacylglycerol lipase


Docosahexaenoic acid






Endocannabinoid membrane transporter


Eicosapentaenoic acid




Fatty acid amide hydrolase


Fatty acid binding protein


FAAH-like anandamide transporter




G-protein coupled receptor




Human embryonic kidney




Heat shock protein








Monoacylglycerol lipase


N-acylethanolamine-selective acid amidase


















N-oleoyl dopamine








Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, cataract




Peroxisome proliferator-activated receptor


Polyunsaturated fatty acid






Transient receptor potential melastatin


Transient receptor potential vanilloid


  1. 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
  2. Berger A, Crozier G, Bisogno T, Cavaliere P, Innis S, Di Marzo V (2001) Anandamide and diet: inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets. Proc Natl Acad Sci U S A 98:6402–6406PubMedCentralPubMedCrossRefGoogle Scholar
  3. Bisogno T, Delton-Vandenbroucke I, Milone A, Lagarde M, Di Marzo V (1999) Biosynthesis and inactivation of N-arachidonoylethanolamine (anandamide) and N-docosahexaenoylethanolamine in bovine retina. Arch Biochem Biophys 370:300–307PubMedCrossRefGoogle Scholar
  4. Bisogno T, Melck D, Bobrov MY, 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 351:817–824PubMedCentralPubMedCrossRefGoogle Scholar
  5. Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, Matias I, Schiano-Moriello A, Paul P, Williams EJ, 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 signaling in the brain. J Cell Biol 163:463–468PubMedCentralPubMedCrossRefGoogle Scholar
  6. Blankman JL, Simon GM, Cravatt BF (2007) A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol 14:1347–1356PubMedCentralPubMedCrossRefGoogle Scholar
  7. 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
  8. Bradshaw HB, Walker JM (2005) The expanding field of cannabimimetic and related lipid mediators. Br J Pharmacol 144:459–465, ReviewPubMedCentralPubMedCrossRefGoogle Scholar
  9. 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
  10. Brown I, Cascio MG, Wahle KW, Smoum R, Mechoulam R, Ross RA, Pertwee RG, Heys SD (2010) Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines. Carcinogenesis 31:1584–1591PubMedCentralPubMedCrossRefGoogle Scholar
  11. Brown I, Wahle KW, Cascio MG, Smoum-Jaouni R, Mechoulam R, Pertwee RG, Heys SD (2011) Omega-3 N-acylethanolamines are endogenously synthesised from omega-3 fatty acids in different human prostate and breast cancer cell lines. Prostaglandins Leukot Essent Fatty Acids 85:305–310PubMedCrossRefGoogle Scholar
  12. Brown I, Cascio MG, Rotondo D, Pertwee RG, Heys SD, Wahle KW (2013) Cannabinoids and omega-3/6 endocannabinoids as cell death and anticancer modulators. Prog Lipid Res 52:80–109, ReviewPubMedCrossRefGoogle Scholar
  13. Cascio MG (2013) PUFA-derived endocannabinoids: an overview. Proc Nutr Soc 72:451–459PubMedCrossRefGoogle Scholar
  14. Cascio MG, Minassi A, Ligresti A, Appendino G, Burstein S, Di Marzo V (2004) A structure-activity relationship study on N-arachidonoyl-amino acids as possible endogenous inhibitors of fatty acid amide hydrolase. Biochem Biophys Res Commun 314:192–196CrossRefGoogle Scholar
  15. Costa B, Comelli F, Bettoni I, Colleoni M, Giagnoni G (2008) The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: involvement of CB(1), TRPV1 and PPARgamma receptors and neurotrophic factors. Pain 139:541–550PubMedCrossRefGoogle Scholar
  16. Cravatt BF, Prospero-Garcia O, Siuzdak G, Gilula NB, Henriksen SJ, Boger DL, Lerner RA (1995) Chemical characterization of a family of brain lipids that induce sleep. Science 268:1506–1509PubMedCrossRefGoogle Scholar
  17. 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
  18. Dalle Carbonare M, Del Giudice E, Stecca A, Colavito D, Fabris M, D’Arrigo A, Bernardini D, Dam M, Leon A (2008) A saturated N-acylethanolamine other than N-palmitoyl ethanolamine with anti-inflammatory properties: a neglected story. J Neuroendocrinol 20(Suppl 1):26–34PubMedCrossRefGoogle Scholar
  19. 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 483:52–56PubMedCrossRefGoogle Scholar
  20. De Petrocellis L, Davis JB, Di Marzo V (2001) Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors. FEBS Lett 506:253–256PubMedCrossRefGoogle Scholar
  21. De Petrocellis L, Starowicz K, Moriello AS, Vivese M, Orlando P, Di Marzo V (2007) Regulation of transient receptor potential channels of melastatin type 8 (TRPM8): effect of cAMP, cannabinoid CB(1) receptors and endovanilloids. Exp Cell Res 313:1911–1920PubMedCrossRefGoogle Scholar
  22. den Boon FS, Chameau P, Schaafsma-Zhao Q, van Aken W, Bari M, Oddi S, Kruse CG, Maccarrone M, Wadman WJ, Werkman TR (2012) Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors. Proc Natl Acad Sci U S A 109:3534–3539CrossRefGoogle Scholar
  23. Desarnaud F, Cadas H, Piomelli D (1995) Anandamide amidohydrolase activity in rat brain microsomes. Identification and partial characterization. J Biol Chem 270:6030–6035PubMedCrossRefGoogle Scholar
  24. 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
  25. Devane WA, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34:605–613PubMedGoogle Scholar
  26. 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 258:1946–1949PubMedCrossRefGoogle Scholar
  27. Di Cesare ML, D’Agostino G, Pacini A, Russo R, Zanardelli M, Ghelardini C, Calignano A (2013) Palmitoylethanolamide is a disease-modifying agent in peripheral neuropathy: pain relief and neuroprotection share a PPAR-alpha-mediated mechanism. Mediators Inflamm 2013:328797Google Scholar
  28. Di Marzo V, Deutsch DG (1998) Biochemistry of the endogenous ligands of cannabinoid receptors. Neurobiol Dis 5:386–404PubMedCrossRefGoogle Scholar
  29. 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 372:686–691PubMedCrossRefGoogle Scholar
  30. Di Marzo V, De Petrocellis L, Bisogno T, Melck D (1999) Metabolism of anandamide and 2-arachidonoylglycerol: an historical overview and some recent developments. Lipids 34(Suppl):S319–S325, ReviewPubMedCrossRefGoogle Scholar
  31. Di Marzo V, De Petrocellis L, Bisogno T (2001) Endocannabinoids Part I: molecular basis of endocannabinoid formation, action and inactivation and development of selective inhibitors. Expert Opin Ther Targets 5:241–265PubMedCrossRefGoogle Scholar
  32. Di Marzo V, Griffin G, De Petrocellis L, Brandi I, Bisogno T, Williams W, Grier MC, Kulasegram S, Mahadevan A, Razdan RK, Martin BR (2002) A structure/activity relationship study on arvanil, an endocannabinoid and vanilloid hybrid. J Pharmacol Exp Ther 300:984–991PubMedCrossRefGoogle Scholar
  33. Di Marzo V, Bifulco M, De Petrocellis L (2004) The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 3:771–784, ReviewPubMedCrossRefGoogle Scholar
  34. Di Pasquale E, Chahinian H, Sanchez P, Fantini J (2009) The insertion and transport of anandamide in synthetic lipid membranes are both cholesterol-dependent. PLoS One 4, e4989PubMedCentralPubMedCrossRefGoogle Scholar
  35. Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathuria S, Piomelli D (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci U S A 99:10819–10824PubMedCentralPubMedCrossRefGoogle Scholar
  36. Egertová 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 Biol Sci 265:2081–2085PubMedCentralPubMedCrossRefGoogle Scholar
  37. Esposito G, Capoccia E, Turco F, Palumbo I, Lu J, Steardo A, Cuomo R, Sarnelli G, Steardo L (2014) Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-α activation. Gut 63:1300–1312PubMedCrossRefGoogle Scholar
  38. Fegley D, Kathuria S, Mercier R, Li C, Goutopoulos A, Makriyannis A, Piomelli D (2004) Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172. Proc Natl Acad Sci U S A 101:8756–8761PubMedCentralPubMedCrossRefGoogle Scholar
  39. Fegley D, Gaetani S, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2005) Characterization of the fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3’-carbamoyl-biphenyl-3-yl ester (URB597): effects on anandamide and oleoylethanolamide deactivation. J Pharmacol Exp Ther 313:352–358PubMedCrossRefGoogle Scholar
  40. 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
  41. Fezza F, Oddi S, Di Tommaso M, De Simone C, Rapino C, Pasquariello N, Dainese E, Finazzi-Agrò A, Maccarrone M (2008) Characterization of biotin-anandamide, a novel tool for the visualization of anandamide accumulation. J Lipid Res 49:1216–1223PubMedCrossRefGoogle Scholar
  42. Fezza F, Bari M, Florio R, Talamonti E, Feole M, Maccarrone M (2014) Endocannabinoids, related compounds and their metabolic routes. Molecules 19:17078–17106, ReviewPubMedCrossRefGoogle Scholar
  43. Fiskerstrand T, H’mida-Ben Brahim D, Johansson S, M’zahem A, Haukanes BI, Drouot N, Zimmermann J, Cole AJ, Vedeler C, Bredrup C, Assoum M, Tazir M, Klockgether T, Hamri A, Steen VM, Boman H, Bindoff LA, Koenig M, Knappskog PM (2010) Mutations in ABHD12 cause the neurodegenerative disease PHARC: an inborn error of endocannabinoid metabolism. Am J Hum Genet 7:410–417CrossRefGoogle Scholar
  44. Fonseca BM, Costa MA, Almada M, Correia-da-Silva G, Teixeira NA (2013) Endogenous cannabinoids revisited: a biochemistry perspective. Prostaglandins Other Lipid Mediat 102–103:13–30, ReviewPubMedCrossRefGoogle Scholar
  45. Fowler CJ (2012) Anandamide uptake explained? Trends Pharmacol Sci 33:181–185, ReviewPubMedCrossRefGoogle Scholar
  46. Fowler CJ (2013) Transport of endocannabinoids across the plasma membrane and within the cell. FEBS J 280:1895–1904, ReviewPubMedCrossRefGoogle Scholar
  47. Fu J, Bottegoni G, Sasso O, Bertorelli R, Rocchia W, Masetti M, Guijarro A, Lodola A, Armirotti A, Garau G, Bandiera T, Reggiani A, Mor M, Cavalli A, Piomelli D (2012) A catalytically silent FAAH-1 variant drives anandamide transport in neurons. Nat Neurosci 15:64–69CrossRefGoogle Scholar
  48. Gao Y, Vasilyev DV, Goncalves MB, Howell FV, Hobbs C, Reisenberg M, Shen R, Zhang MY, Strassle BW, Lu P, Mark L, Piesla MJ, Deng K, Kouranova EV, Ring RH, Whiteside GT, Bates B, Walsh FS, Williams G, Pangalos MN, Samad TA, Doherty P (2010) Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice. J Neurosci 30:2017–2024PubMedCrossRefGoogle Scholar
  49. Ghafouri N, Ghafouri B, Larsson B, Stensson N, Fowler CJ, Gerdle B (2013) Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain correlate with pain intensity and sensitivity. Pain 154:1649–1658PubMedCrossRefGoogle Scholar
  50. Ghosh S, Wise LE, Chen Y, Gujjar R, Mahadevan A, Cravatt BF, Lichtman AH (2013) The monoacylglycerol lipase inhibitor JZL184 suppresses inflammatory pain in the mouse carrageenan model. Life Sci 92:498–505PubMedCentralPubMedCrossRefGoogle Scholar
  51. Giang DK, Cravatt BF (1997) Molecular characterization of human and mouse fatty acid amide hydrolases. Proc Natl Acad Sci U S A 94:2238–2242PubMedCentralPubMedCrossRefGoogle Scholar
  52. Gulyas AI, Cravatt BF, Bracey MH, Dinh TP, Piomelli D, Boscia F, Freund TF (2004) Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci 20:441–458PubMedCrossRefGoogle Scholar
  53. Hanus LO (2007) Discovery and isolation of anandamide and other endocannabinoids. Chem Biodivers 4:1828–1841PubMedCrossRefGoogle Scholar
  54. 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 U S A 98:3662–3665PubMedCentralPubMedCrossRefGoogle Scholar
  55. Hillard CJ, Jarrahian A (2000) The movement of N-arachidonoylethanolamine (anandamide) across cellular membranes. Chem Phys Lipids 108:123–134, ReviewPubMedCrossRefGoogle Scholar
  56. Ho WS, Hillard CJ (2005) Modulators of endocannabinoid enzymic hydrolysis and membrane transport. Handb Exp Pharmacol 168:187–207, ReviewPubMedCrossRefGoogle Scholar
  57. Ho WS, Barrett DA, Randall MD (2008) ‘Entourage’ effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors. Br J Pharmacol 155:837–846PubMedCentralPubMedCrossRefGoogle Scholar
  58. 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 U S A 99:8400–8405PubMedCentralPubMedCrossRefGoogle Scholar
  59. Kaczocha M, Glaser ST, Deutsch DG (2009) Identification of intracellular carriers for the endocannabinoid anandamide. Proc Natl Acad Sci U S A 106:6375–6380PubMedCentralPubMedCrossRefGoogle Scholar
  60. 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 272:27218–27223PubMedCrossRefGoogle Scholar
  61. Katayama K, Ueda N, Kurahashi Y, Suzuki H, Yamamoto S, Kato I (1997) Distribution of anandamide amidohydrolase in rat tissues with special reference to small intestine. Biochim Biophys Acta 1347:212–218PubMedCrossRefGoogle Scholar
  62. Kathuria S, Gaetani S, Fegley D, Valiño 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
  63. Kohno M, Hasegawa H, Inoue A, Muraoka M, Miyazaki T, Oka K, Yasukawa M (2006) Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18. Biochem Biophys Res Commun 347:827–832PubMedCrossRefGoogle Scholar
  64. Leggett JD, Aspley S, Beckett SR, D’Antona AM, Kendall DA, Kendall DA (2004) Oleamide is a selective endogenous agonist of rat and human CB1 cannabinoid receptors. Br J Pharmacol 141:253–262PubMedCentralPubMedCrossRefGoogle Scholar
  65. 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
  66. Ligresti A, Morera E, Van Der Stelt M, 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 380:265–272PubMedCentralPubMedCrossRefGoogle Scholar
  67. Liu Q, Tonai T, Ueda N (2002) Activation of N-acylethanolamine-releasing phospholipase D by polyamines. Chem Phys Lipids 115:77–84PubMedCrossRefGoogle Scholar
  68. Liu J, Wang L, Harvey-White J, Osei-Hyiaman D, Razdan R, Gong Q, Chan AC, Zhou Z, Huang BX, Kim HY, Kunos G (2006) A biosynthetic pathway for anandamide. Proc Natl Acad Sci U S A 103:13345–13350PubMedCentralPubMedCrossRefGoogle Scholar
  69. Lo Verme J, Fu J, Astarita G, La Rana G, Russo R, Calignano A, Piomelli D (2005) The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Mol Pharmacol 67:15–19PubMedCrossRefGoogle Scholar
  70. López-Rodríguez ML, Viso A, Ortega-Gutiérrez S, Lastres-Becker I, González S, Fernández-Ruiz J, Ramos JA (2001) Design, synthesis and biological evaluation of novel arachidonic acid derivatives as highly potent and selective endocannabinoid transporter inhibitors. J Med Chem 44:4505–4508PubMedCrossRefGoogle Scholar
  71. Maccarrone M, Cartoni A, Parolaro D, Margonelli A, Massi P, Bari M, Battista N, Finazzi-Agrò A (2002) Cannabimimetic activity, binding, and degradation of stearoylethanolamide within the mouse central nervous system. Mol Cell Neurosci 21:126–140PubMedCrossRefGoogle Scholar
  72. Maccarrone M, Di Rienzo M, Finazzi-Agrò A, Rossi A (2003a) Leptin activates the anandamide hydrolase promoter in human T lymphocytes through STAT3. J Biol Chem 278:13318–13324PubMedCrossRefGoogle Scholar
  73. Maccarrone M, Bari M, Di Rienzo M, Finazzi-Agrò A, Rossi A (2003b) 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 278:32726–32732PubMedCrossRefGoogle Scholar
  74. Maccarrone M, Dainese E, Oddi S (2010) Intracellular trafficking of anandamide: new concepts for signaling. Trends Biochem Sci 35:601–608PubMedCrossRefGoogle Scholar
  75. McHugh D, Roskowski D, Xie S, Bradshaw HB (2014) Δ(9)-THC and N-arachidonoyl glycine regulate BV-2 microglial morphology and cytokine release plasticity: implications for signaling at GPR18. Front Pharmacol 4:162PubMedCentralPubMedCrossRefGoogle Scholar
  76. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR et al (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90PubMedCrossRefGoogle Scholar
  77. 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
  78. Moriconi A, Cerbara I, Maccarrone M, Topai A (2010) GPR55: current knowledge and future perspectives of a purported “Type-3” cannabinoid receptor. Curr Med Chem 17:1411–1429, ReviewPubMedCrossRefGoogle Scholar
  79. Oddi S, Fezza F, Pasquariello N, De Simone C, Rapino C, Dainese E, Finazzi-Agrò A, Maccarrone M (2008) Evidence for the intracellular accumulation of anandamide in adiposomes. Cell Mol Life Sci 65:840–850PubMedCrossRefGoogle Scholar
  80. Oddi S, Fezza F, Pasquariello N, D’Agostino A, Catanzaro G, De Simone C, Rapino C, Finazzi-Agrò A, Maccarrone M (2009) Molecular identification of albumin and Hsp70 as cytosolic anandamide-binding proteins. Chem Biol 16:624–632PubMedCrossRefGoogle Scholar
  81. Oh DY, Yoon JM, Moon MJ, Hwang JI, Choe H, Lee JY, Kim JI, Kim S, Rhim H, O’Dell DK, Walker JM, Na HS, Lee MG, Kwon HB, Kim K, Seong JY (2008) Identification of farnesyl pyrophosphate and N-arachidonylglycine as endogenous ligands for GPR92. J Biol Chem 283:21054–21064PubMedCentralPubMedCrossRefGoogle Scholar
  82. Oka S, Tsuchie A, Tokumura A, Muramatsu M, Suhara Y, Takayama H, Waku K, 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
  83. 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
  84. 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
  85. O’Sullivan SE (2007) Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol 152:576–582, ReviewPubMedCentralPubMedCrossRefGoogle Scholar
  86. Overton HA, Fyfe MC, Reynet C (2008) GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity. Br J Pharmacol 153(Suppl 1):S76–S81, ReviewPubMedCentralPubMedGoogle Scholar
  87. Páldyová E, Bereczki E, Sántha M, Wenger T, Borsodi A, Benyhe S (2008) Noladin ether, a putative endocannabinoid, inhibits mu-opioid receptor activation via CB2 cannabinoid receptors. Neurochem Int 52:321–328PubMedCrossRefGoogle Scholar
  88. Pertwee RG (2005) The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids. AAPS J 7:E625–E654, ReviewPubMedCentralPubMedCrossRefGoogle Scholar
  89. Pertwee RG (2014) Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications. Proc Nutr Soc 73:96–105PubMedCrossRefGoogle Scholar
  90. Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA (2010) International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev 62:588–631, ReviewPubMedCentralPubMedCrossRefGoogle Scholar
  91. Petersen G, Hansen HS (1999) N-acylphosphatidylethanolamine-hydrolysing phospholipase D lacks the ability to transphosphatidylate. FEBS Lett 455:41–44PubMedCrossRefGoogle Scholar
  92. Petrosino S, Di Marzo V (2010) FAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels. Curr Opin Investig Drugs 11:51–62, ReviewPubMedGoogle Scholar
  93. Petrosino S, Iuvone T, Di Marzo V (2010) N-palmitoyl-ethanolamine: biochemistry and new therapeutic opportunities. Biochimie 92:724–727, ReviewPubMedCrossRefGoogle Scholar
  94. Piomelli D (2014) More surprises lying ahead. The endocannabinoids keep us guessing. Neuropharmacology 76(Pt B):228–234, ReviewPubMedCrossRefGoogle Scholar
  95. Piscitelli F, Di Marzo V (2012) “Redundancy” of endocannabinoid inactivation: new challenges and opportunities for pain control. ACS Chem Neurosci 3:356–363, ReviewPubMedCentralPubMedCrossRefGoogle Scholar
  96. 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 endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther 301:1020–1024PubMedCrossRefGoogle Scholar
  97. Puffenbarger RA, Kapulina O, Howell JM, Deutsch DG (2001) Characterization of the 5′-sequence of the mouse fatty acid amide hydrolase. Neurosci Lett 314:21–24PubMedCrossRefGoogle Scholar
  98. Rodríguez de Fonseca F (2004) The endocannabinoid system and food intake control. Rev Med Univ Navarra 48(2):18–23PubMedGoogle Scholar
  99. Rozenfeld R, Devi LA (2008) Regulation of CB1 cannabinoid receptor trafficking by the adaptor protein AP-3. FASEB J 22:2311–2322PubMedCentralPubMedCrossRefGoogle Scholar
  100. Saario SM, Savinainen JR, Laitinen JT, Järvinen T, Niemi R (2004) Monoglyceride lipase-like enzymatic activity is responsible for hydrolysis of 2-arachidonoylglycerol in rat cerebellar membranes. Biochem Pharmacol 67:1381–1387PubMedCrossRefGoogle Scholar
  101. Saario SM, Salo OM, Nevalainen T, Poso A, Laitinen JT, Järvinen T, Niemi R (2005) Characterization of the sulfhydryl-sensitive site in the enzyme responsible for hydrolysis of 2-arachidonoyl-glycerol in rat cerebellar membranes. Chem Biol 12:649–656PubMedCrossRefGoogle Scholar
  102. Savinainen JR, Yoshino M, Minkkilä A, Nevalainen T, Laitinen JT (2010) Characterization of binding properties of monoglyceride lipase inhibitors by a versatile fluorescence-based technique. Anal Biochem 399:132–134PubMedCrossRefGoogle Scholar
  103. Savinainen JR, Saario SM, Laitinen JT (2012) The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors. Acta Physiol (Oxf) 204:267–276CrossRefGoogle Scholar
  104. Schlosburg JE, Blankman JL, Long JZ, Nomura DK, Pan B, Kinsey SG, Nguyen PT, Ramesh D, Booker L, Burston JJ, Thomas EA, Selley DE, Sim-Selley LJ, Liu QS, Lichtman AH, Cravatt BF (2010) Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat Neurosci 13:1113–1119PubMedCentralPubMedCrossRefGoogle Scholar
  105. Sharir H, Console-Bram L, Mundy C, Popoff SN, Kapur A, Abood ME (2012) The endocannabinoids anandamide and virodhamine modulate the activity of the candidate cannabinoid receptor GPR55. J Neuroimmune Pharmacol 7:856–865PubMedCentralPubMedCrossRefGoogle Scholar
  106. Sheskin T, Hanus L, Slager J, Vogel Z, Mechoulam R (1997) Structural requirements for binding of anandamide-type compounds to the brain cannabinoid receptor. J Med Chem 40:659–667PubMedCrossRefGoogle Scholar
  107. Sigel E, Baur R, Rácz I, Marazzi J, Smart TG, Zimmer A, Gertsch J (2011) The major central endocannabinoid directly acts at GABA(A) receptors. Proc Natl Acad Sci U S A 108:18150–18155PubMedCentralPubMedCrossRefGoogle Scholar
  108. Simon GM, Cravatt BF (2006) Endocannabinoid biosynthesis proceeding through glycerophospho-N-acyl ethanolamine and a role for alpha/beta-hydrolase 4 in this pathway. J Biol Chem 281:26465–26472PubMedCrossRefGoogle Scholar
  109. 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
  110. Sugiura T, Kondo S, Sukagawa A, Tonegawa T, Nakane S, Yamashita A, Waku K (1996) N-arachidonoylethanolamine (anandamide), an endogenous cannabinoid receptor ligand, and related lipid molecules in the nervous tissues. J Lipid Mediat Cell Signal 14:51–56, ReviewPubMedCrossRefGoogle Scholar
  111. 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 380:749–756PubMedCentralPubMedCrossRefGoogle Scholar
  112. Sun YX, Tsuboi K, Zhao LY, Okamoto Y, Lambert DM, Ueda N (2005) Involvement of N-acylethanolamine-hydrolyzing acid amidase in the degradation of anandamide and other N-acylethanolamines in macrophages. Biochim Biophys Acta 1736:211–220PubMedCrossRefGoogle Scholar
  113. Sun Y, Alexander SP, Kendall DA, Bennett AJ (2006) Cannabinoids and PPARalpha signalling. Biochem Soc Trans 34:1095–1097PubMedCrossRefGoogle Scholar
  114. Tanimura A, Yamazaki M, Hashimotodani Y, Uchigashima M, Kawata S, Abe M, Kita Y, Hashimoto K, Shimizu T, Watanabe M, Sakimura K, Kano M (2010) The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase alpha mediates retrograde suppression of synaptic transmission. Neuron 65:320–327PubMedCrossRefGoogle Scholar
  115. Ueda N (2002) Endocannabinoid hydrolases. Prostaglandins Other Lipid Mediat 68–69:521–534, ReviewPubMedCrossRefGoogle Scholar
  116. Ueda N, Kurahashi Y, Yamamoto K, Yamamoto S, Tokunaga T (1996) Enzymes for anandamide biosynthesis and metabolism. J Lipid Mediat Cell Signal 14:57–61PubMedCrossRefGoogle Scholar
  117. Ueda N, Yamanaka K, Terasawa Y, Yamamoto S (1999) An acid amidase hydrolyzing anandamide as an endogenous ligand for cannabinoid receptors. FEBS Lett 454:267–270PubMedCrossRefGoogle Scholar
  118. Ueda N, Liu Q, Yamanaka K (2001a) Marked activation of the N-acylphosphatidylethanolamine-hydrolyzing phosphodiesterase by divalent cations. Biochim Biophys Acta 1532:121–127PubMedCrossRefGoogle Scholar
  119. 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 276:35552–35557PubMedCrossRefGoogle Scholar
  120. Ueda N, Tsuboi K, Uyama T (2010) N-acylethanolamine metabolism with special reference to N-acylethanolamine-hydrolyzing acid amidase (NAAA). Prog Lipid Res 49:299–315, ReviewPubMedCrossRefGoogle Scholar
  121. Ueda N, Tsuboi K, Uyama T (2013) Metabolism of endocannabinoids and related N-acylethanolamines: canonical and alternative pathways. FEBS J 280:1874–1894PubMedCrossRefGoogle Scholar
  122. 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
  123. Wei BQ, Mikkelsen TS, McKinney MK, Lander ES, Cravatt BF (2006) A second fatty acid amide hydrolase with variable distribution among placental mammals. J Biol Chem 281:36569–36578PubMedCrossRefGoogle Scholar
  124. 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 160:481–486PubMedCentralPubMedCrossRefGoogle Scholar
  125. Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sørgård M, Di Marzo V, Julius D, Högestätt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400:452–457PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.School of Medical Sciences, Institute of Medical SciencesUniversity of AberdeenAberdeenScotland, UK

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