Skip to main content
SpringerLink
Log in
Book cover

Cannabinoids and the Brain pp 31–46Cite as

Removal of Endocannabinoids by the Body: Mechanisms and Therapeutic Possibilities

  • Chapter

  • 1524 Accesses

The actions of anandamide and 2-arachidonoylglycerol are terminated by cellular uptake followed by metabolism. In the case of anandamide, the uptake process was originally suggested to be achieved by a process of facilitated diffusion, but the mechanism(s) involved are a matter of controversy at present. The main hydrolytic enzyme for anandamide is fatty acid amide hydrolase, and inhibitors of this enzyme have been found to have beneficial effects in animal models of inflammatory pain, inflammation, anxiety and depression. Anandamide is also a substrate for cyclooxygenase-2 and lipoxygenases, and the cyclooxygenase-derived products, the “prostamides” have biological actions of their own. 2-Arachidonoylglycerol can be metabolized by a range of enzymes, including cyclooxygenase-2, monoacylglycerol lipase and fatty acid amide hydrolase. In the brain, monoacylglycerol lipase is probably the most important of these enzymes. However, no selective inhibitors of this enzyme are presently available with which to establish the potential of this enzyme as a target for drug development.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Alexander JP, Cravatt BF (2006) The putative endocannabinoid transport blocker LY2183240 is a potent inhibitor of FAAH and several other brain serine hydrolases. J Am Chem Soc 128:9699–9704.

    Article  PubMed  CAS  Google Scholar 

  • Ates M, Hamza M, Seidel K, Kotalla CE, Ledent C, Gühring H (2003) Intrathecally applied flurbiprofen produces an endocannabinoid-dependent antinociception in the rat formalin test. Eur J Neurosci 17:597–604.

    Article  PubMed  Google Scholar 

  • Bari M, Battista N, Fezza F, Finazzi-Agrò A, Maccarrone M (2005) Lipid rafts control signaling of type-1 cannabinoid receptors in neuronal cells. Implications for anandamide-induced apoptosis. J Biol Chem 280:12212–12220.

    Article  PubMed  CAS  Google Scholar 

  • Bari M, Spagnuolo P, Fezza F, Oddi S, Pasquariello N, Finazzi-Agrò A, Maccarrone M (2006) Effect of lipid rafts on Cb2 receptor signaling and 2-arachidonoyl-glycerol metabolism in human immune cells. J Immunol 177:4971–4980.

    PubMed  CAS  Google Scholar 

  • Beltramo M, Piomelli D (2000) Carrier-mediated transport and enzymatic hydrolysis of the endogenous cannabinoid 2-arachidonylglycerol. Neuroreport 11:1231–1235.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Bifulco M, Laezza C, Valenti M, Ligresti A, Portella G, Di Marzo V (2004) A new strategy to block tumor growth by inhibiting endocannabinoid inactivation. FASEB J 18:1606–1608.

    PubMed  CAS  Google Scholar 

  • Bilsland LG, Dick JRT, Pryce G, Petrosino S, Di Marzo V, Baker D, Greensmith L (2006) Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice. FASEB J 20:1003–1005; full article E180–E190.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Blednov YA, Cravatt BF, Boehm SL, Walker D, Harris RA (2007) Role of endocannabinoids in alcohol consumption and intoxication: studies of mice lacking fatty acid amide hydrolase. Neuropsychopharmacology, doi:10.1038/sj.npp. 1301274.

    Google Scholar 

  • Bojesen IN, Hansen HS (2005) Membrane transport of anandamide through resealed human red blood cell membranes. J Lipid Res 46:1652–1659.

    Article  PubMed  CAS  Google Scholar 

  • Chang L, Luo L, Palmer JA, Sutton S, Wilson SJ, Barbier AJ, Breitenbucher JG, Chaplan SR, Webb M (2006) Inhibition of fatty acid amide hydrolase produces analgesia by multiple mechanisms. Br J Pharmacol 148:102–113.

    Article  PubMed  CAS  Google Scholar 

  • Chiang KP, Gerber AL, Sipe JC, Cravatt BF (2004) Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use. Hum Mol Genet 13:2113–2119.

    Article  PubMed  CAS  Google Scholar 

  • Clapper JR, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2006) The fatty-acid amide hydrolase inhibitor URB597 does not affect triacylglycerol hydrolysis in rat tissues. Pharmacol Res 54:341–344.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Compton DR, Martin BR (1997) The effect of the enzyme inhibitor phenylmethylsulfonyl fluoride on the pharmacological effect of anandamide in the mouse model of cannabimimetic activity. J Pharmacol Exp Ther 283:1138–1143.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Cravatt BF, Saghatelian A, Hawkins EG, Clement AB, Bracey MH, Lichtman AH (2004) Functional disassociation of the central and peripheral fatty acid amide signaling systems. Proc Natl Acad Sci USA 101:10821–10826.

    Article  PubMed  CAS  Google Scholar 

  • D’Argenio G, Valenti M, Scaglione G, Cosenza V, Sorrentini I, Di Marzo V (2006) Up-regulation of anandamide levels as an endogenous mechanism and a pharmacological strategy to limit colon inflammation. FASEB J 20:568–570.

    PubMed  Google Scholar 

  • Deutsch DG, Chin SA (1993) Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. Biochem Pharmacol 46:791–796.

    Article  PubMed  CAS  Google Scholar 

  • 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 (FAAH). J Biol Chem 276:6967–6973.

    Article  PubMed  CAS  Google Scholar 

  • Dickason-Chesterfield AK, Kidd SR, Moore SA, Schaus JM, Liu B, Nomikos GG, Felder CC (2006) Pharmacological characterization of endocannabinoid transport and fatty acid amide hydrolase inhibitors. Cell Mol Neurobiol 26:405–421.

    Article  CAS  Google Scholar 

  • Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz J-C, Piomelli D (1994) Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372:686–691.

    Article  PubMed  CAS  Google Scholar 

  • 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 USA 99:10819–10824.

    Article  PubMed  CAS  Google Scholar 

  • Dinh TP, Kathuria S, Piomelli D (2004) RNA interference suggests a primary role for monoacylglycerol lipase in the degradation of the endocannabinoid 2-arachidonoylglycerol. Mol Pharmacol 66:1260–1264.

    Article  PubMed  CAS  Google Scholar 

  • Ehehalt R, Füllekrug J, Pohl J, Ring A, Herrmann T, Stremmel W (2006) Translocation of long chain fatty acids across the plasma membrane–lipid rafts and fatty acid transport proteins. Mol Cell Biochem 284:135–140.

    Article  PubMed  CAS  Google Scholar 

  • 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 USA 101:8756–8761.

    Article  PubMed  CAS  Google Scholar 

  • Flanagan JM, Gerber AL, Cadet JL, Beutler E, Sipe JC (2006) The fatty acid amide hydrolase 385 A/A (P129T) variant: haplotype analysis of an ancient missense mutation and validation of risk for drug addiction. Hum Genet 120:581–588.

    Article  PubMed  CAS  Google Scholar 

  • Fowler CJ (2006) The cannabinoid system and its pharmacological manipulation–a review, with emphasis upon the uptake and hydrolysis of anandamide. Fundam Clin Pharmacol 20:549–562.

    Article  PubMed  CAS  Google Scholar 

  • Fowler CJ, Tiger G (2005) Cyclooxygenation of the arachidonoyl side chain of 1-arachidonoylglycerol and related compounds block their ability to prevent anandamide and 2-oleoylglycerol metabolism by rat brain in vitro. Biochem Pharmacol 69:1241–1245.

    Article  PubMed  CAS  Google Scholar 

  • Fowler CJ, Tiger G, Stenström A (1997) Ibuprofen inhibits rat brain deamidation of anandamide at pharmacologically relevant concentrations. Mode of inhibition and structure-activity relationship. J Pharmacol Exp Ther 283:729–734.

    PubMed  CAS  Google Scholar 

  • Fowler CJ, Holt S, Tiger G (2003) Acidic nonsteroidal anti-inflammatory drugs inhibit rat brain fatty acid amide hydrolase in a pH-dependent manner. J Enz Inhib Med Chem 18:55–58.

    Article  CAS  Google Scholar 

  • Fowler CJ, Tiger G, Ligresti A, López-Rodíguez 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.

    Article  PubMed  CAS  Google Scholar 

  • Fowler CJ, Holt S, Nilsson O, Jonsson K-O, Tiger G, Jacobson SOP (2005) The endocannabinoid signaling system: pharmacological and therapeutic aspects. Pharmacol Biochem Behav 81:248–262.

    Article  PubMed  CAS  Google Scholar 

  • Fu J, Gaetani S, Oveisi F, Lo Verme J, Serrano A, Rodríguez de Fonseca F, Rosengath A, Luecke H, Di Giacomo B, Tarzia G, Piomelli D (2003) Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-H. Nature 425:90–93.

    Article  PubMed  CAS  Google Scholar 

  • Gobbi G, Bambico FR, Mangieri R, Bortolato M, Campolongo P, Solinas M, Cassano T, Morgese MG, Debonnel G, Duranti A, Tontini A, Tarzia G, Mor M, Trezza V, Goldberg SR, Cuomo V, Piomelli D (2005) Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc Natl Acad Sci USA 102:18620–18625.

    Article  PubMed  CAS  Google Scholar 

  • Goparaju SK, Ueda N, Yamaguchi H, Yamamoto S (1998) Anandamide amidohydrolase reacting with 2-arachidonoylglycerol, another cannabinoid receptor ligand. FEBS Lett 422:69–73.

    Article  PubMed  CAS  Google Scholar 

  • Gühring H, Hamza M, Sergejeva M, Ates M, Kotalla CE, Ledent C, Brune K (2002) A role for endocannabinoids in indomethacin-induced spinal antinociception. Eur J Pharmacol 454:153–163.

    Article  PubMed  Google Scholar 

  • Guindon J, De Léan A, Beaulieu P (2006a) Local interactions between anandamide, an endocannabinoid, and ibuprofen, a nonsteroidal anti-inflammatory drug, in acute and inflammatory pain. Pain 121:85–93.

    Article  PubMed  CAS  Google Scholar 

  • Guindon J, LoVerme J, De Léan A, Piomelli D, Beaulieu P (2006b) Synergistic antinociceptive effects of anandamide, an endocannabinoid, and nonsteroidal anti-inflammatory drugs in peripheral tissue: a role for endogenous fatty-acid ethanolamides? Eur J Pharmacol 550:68–77.

    Article  PubMed  CAS  Google Scholar 

  • 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 20:441–458.

    Article  PubMed  CAS  Google Scholar 

  • Habayeb OMH, Taylor AH, Evans MD, Cooke MS, Taylor DJ, Bell SC, Konje JC (2004) Plasma levels of the endocannabinoid anandamide in women–a potential role in pregnancy maintenance and labor? J Clin Endocrinol Metab 89:5482–5487.

    Article  PubMed  CAS  Google Scholar 

  • Hájos N, Kathuria S, Dinh T, Piomelli D, Freund TF (2004) Endocannabinoid transport tightly controls 2-arachidonoyl glycerol actions in the hippocampus: effects of low temperature and the transport inhibitor AM404. Eur J Neurosci 19:2991–2996.

    Article  PubMed  Google Scholar 

  • Hansson AC, Bermúdez-Silva FJ, Malinen H, Hyytiä P, Sanchez-Vera I, Rimondini R, Rodriguez de Fonseca F, Kunos G, Sommer WH, Heilig M (2007) Genetic impairment of frontocortical endocannabinoid degradation and high alcohol preference. Neuropsychopharmacology 32:117–126.

    Article  PubMed  CAS  Google Scholar 

  • Hashimotodani Y, Ohno-Shosaku T, Kano M (2007) Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus. J Neurosci 27:1211–1219.

    Article  PubMed  CAS  Google Scholar 

  • Hermann A, Kaczocha M, Deutsch DG (2006) 2-Arachidonoylglycerol (2-AG) membrane transport: history and outlook. AAPS J 8:E409–E412.

    PubMed  Google Scholar 

  • Hillard CJ, Jarrahian A (2000) The movement of N-arachidonoylethanolamine (anandamide) across cellular membranes. Chem Phys Lipids 108:123–134.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Högestätt ED, Jönsson BAG, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM (2005) Conversion of acetaminophen to the bioactive N-acyl phenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 280:31405–31412.

    Article  PubMed  CAS  Google Scholar 

  • Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2005) An endocannabinoid mechanism for stress-induced analgesia. Nature 435:1108–1112.

    Article  PubMed  CAS  Google Scholar 

  • Holt S, Comelli F, Costa B, Fowler CJ (2005) Inhibitors of fatty acid amide hydrolase reduce carrageenan-induced hind paw inflammation in pentobarbital-treated mice: comparison with indomethacin and possible involvement of cannabinoid receptors. Br J Pharmacol 146:467–476.

    Article  PubMed  CAS  Google Scholar 

  • 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 75:2597–2606.

    Article  Google Scholar 

  • Jayamanne A, Greenwood R, Mirtchell VA, Aslan S, Piomelli D, Vaughan CW (2006) Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models. Br J Pharmacol 147:281–288.

    Article  PubMed  CAS  Google Scholar 

  • Jensen DP, Andreasen CH, Andersen MK, Hansen L, Eiberg H, Borch-Johnsen K, Jørgensen T, Hansen T, Pedersen O (2007) The functional Pro129Thr variant of the FAAH gene is not associated with various fat accumulation phenotypes in a population-based cohort of 5, 801 whites. J Mol Med 85:445–449.

    Article  PubMed  CAS  Google Scholar 

  • Jerman JC, Gray J, Brough SJ, Ooi L, Owen D, Davis JB, Smart D (2002) Comparison of effects of anandamide at recombinant and endogenous rat vanilloid receptors. Br J Anaesth 89:882–887.

    Article  PubMed  CAS  Google Scholar 

  • Jhaveri MD, Richardson D, Kendall DA, Barrett DA, Chapman V (2006) Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain. J Neurosci 26:13318–13327.

    Article  PubMed  CAS  Google Scholar 

  • Jordt S-E, Julius D (2002) Molecular basis for species-specific sensitivity to “hot” chili peppers. Cell 108:421–430.

    Article  PubMed  CAS  Google Scholar 

  • Kaczocha M, Hermann A, Glaser ST, Bojesen IN, Deutsch DG (2006) Anandamide uptake is consistent with rate-limited diffusion and is regulated by the degree of its hydrolysis by fatty acid amide hydrolase. J Biol Chem 281:9066–9075.

    Article  PubMed  CAS  Google Scholar 

  • Kage KL, Richardson PL, Traphagen L, Severin J, Pereda-Lopez A, Lubben T, Davis-Taber R, Vos MH, Bartley D, Walter K, Harlan J, Solomon L, Warrior U, Holzman TF, Faltynek C, Surowy CS, Scott VE (2007) A high throughput fluorescent assay for measuring the activity of fatty acid amide hydrolase. J Neurosci Methods 161:47–54.

    Article  PubMed  CAS  Google Scholar 

  • 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 9:76–81.

    Article  PubMed  CAS  Google Scholar 

  • Kim J, Alger BE (2004) Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in hippocampus. Nat Neurosci 7:697–698.

    Article  PubMed  CAS  Google Scholar 

  • Kozak KR, Marnett LJ (2002) Oxidative metabolism of endocannabinoids. Prostaglandins Leukot Essent Fatty Acids 66:211–220.

    Article  PubMed  CAS  Google Scholar 

  • Lang W, Qin C, Lin S, Khanolkar AD, Goutopoulos A, Fan P, Abouzid K, Meng Z, Biegel D, Makriyannis A. (1999) Substrate specificity and stereoselectivity of rat brain microsomal anandamide amidohydrolase. J Med Chem 42:896–902.

    Article  PubMed  CAS  Google Scholar 

  • La Rana G, Russo R, Campolongo P, Bortolato M, Mangieri RA, Cuomo V, Iacono A, Raso GM, Meli R, Piomelli D, Calignano A (2006) Modulation of neuropathic and inflammatory pain by the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5, 8, 11, 14-tetraenamide]. J Pharmacol Exp Ther 317:1365–1371.

    Article  PubMed  CAS  Google Scholar 

  • Lichtman AH, Leung D, Shelton CC, Saghatelian A, Hardouin C, Boger DL, Cravatt BF (2004a) Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity. J Pharmacol Exp Ther 311:441–448.

    Article  PubMed  CAS  Google Scholar 

  • Lichtman AH, Shelton CC, Advani T, Cravatt BF (2004b) Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. Pain 109:319–327.

    Article  PubMed  CAS  Google Scholar 

  • Ligresti A, Cascio MG, Pryce G, Kulasegram S, Beletskaya I, De Petrocellis L, Saha B, Mahadevan A, Visintin C, Wiley JL, Baker D, Martin BR, Razdan RK, Di Marzo V (2006) New potent and selective inhibitors of anandamide reuptake with antispastic activity in a mouse model of multiple sclerosis. Br J Pharmacol 147:83–91.

    Article  PubMed  CAS  Google Scholar 

  • Lo Verme J, Fu J, Astarita G, La Rana G, Russo R, Calignano A, Piomelli D (2005) The nuclear receptor PPAR-L mediates the antiinflammatory actions of palmitoylethanolamide. Mol Pharmacol 67:15–19.

    Article  PubMed  CAS  Google Scholar 

  • Lo Verme J, Russo R, La Rana G, Fu J, Farthing J, Mattace-Raso G, Meli R, Hohmann A, Calignano A, Piomelli D (2006) Rapid broad-spectrum analgesia through activation of peroxisoma proliferator-activated receptor-t. J Pharmacol Exp Ther 319:1051–1061.

    Article  CAS  Google Scholar 

  • Maccarrone M, Finazzi-Agrò A (2004) Anandamide hydrolase: a guardian angel of human reproduction? Trends Pharmacol Sci 25:353–357.

    Article  PubMed  CAS  Google Scholar 

  • Maccarrone M, Valensise H, Bari M, Lazzarin N, Romanini C, Finazzi-Agrò A (2000) Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage. Lancet 355:1326–1329.

    Article  PubMed  CAS  Google Scholar 

  • Maione S, De Petrocellis L, de Novellis V, Schiano Moriello A, Petrosino S, Palazzo E, Sca Rossi F, Woodward DF, Di Marzo V (2007) Analgesic actions of N-arachidonoyl-serotonin, a fatty acid amide hydrolase inhibitor with antagonistic activity at vanilloid TRPV1 receptors. Br J Pharmacol 150:766–781.

    Article  PubMed  CAS  Google Scholar 

  • Makara JK, Mor M, Fegley D, Szabó SI, Kathuria S, Astarita G, Duranti A, Tontini A, Tarzia G, Rivara S, Freund TF, Piomelli D (2007) Corrigendum: selective inhibition of 2-AG enhances endocannabinoid signaling in hippocampus. Nat Neurosci 10:134. Original article published in 2005 in Nat Neurosci 8:1139–1141.

    Article  CAS  Google Scholar 

  • Marco EM, Adriani W, Canese R, Podo F, Viveros MP, Laviola G (2007) Enhancement of endocannabinoid signalling during adolescence: modulation of impulsivity and long-term consequences on metabolic brain parameters in early maternally deprived rats. Pharmacol Biochem Behav 86:334–345.

    Article  PubMed  CAS  Google Scholar 

  • Massa F, Marsicano G, Hermann H, Cannich A, Monory K, Cravatt BF, Ferri G-L, Sibaev A, Storr M, Lutz B (2004) The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest 113:1202–1209.

    PubMed  CAS  Google Scholar 

  • Matas D, Juknat A, Pietr M, Klin Y, Vogel Z (2007) Anandamide protects from low serum-induced apoptosis via its degradation to ethanolamine. J Biol Chem 282:7885–7892.

    Article  PubMed  CAS  Google Scholar 

  • Matias I, Chen J, De Petrocellis L, Bisogno T, Ligresti A, Fezza F, Krauss AH-P, 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.

    Article  PubMed  CAS  Google Scholar 

  • McFarland MJ, Porter AC, Rakhshan FR, Rawat DS, Gibbs RA, Barker EL (2004) A role for caveolae/lipid rafts in the uptake and recycling of the endogenous cannabinoid anandamide. J Biol Chem 279:41991–41997.

    Article  PubMed  CAS  Google Scholar 

  • McKinney MK, Cravatt BF (2005) Structure and function of fatty acid amide hydrolase. Annu Rev Biochem 74:411–432.

    Article  PubMed  CAS  Google Scholar 

  • Moore SA, Nomikos GG, Dickason-Chesterfield AK, Schober DA, Schaus JM, Ying B-P, Xu Y-C, Phebus L, Simmons RMA, Li D, Iyengar S, Felder CC (2005) Identification of a high-affinity binding site involved in the transport of endocannabinoids. Proc Natl Acad Sci USA 102:17852–17857.

    Article  PubMed  CAS  Google Scholar 

  • Morita Y, Ujike H, Tanaka Y, Uchida N, Nomura A, Ohtani K, Kishimoto M, Morio A, Imamura T, Sakai A, Inada T, Harano M, Komiyama T, Yamada M, Sekine Y, Iwata N, Iyo M, Sora I, Ozaki N, Kuroda S (2005) A nonsynonymous polymorphism in the human fatty acid amide hydrolase gene did not associate with either methamphetamine dependence or schizophrenia. Neurosci Lett 376:182–187.

    Article  PubMed  CAS  Google Scholar 

  • Mulder AH, Cravatt BF (2006) Endocannabinoid metabolism in the absence of fatty acid amide hydrolase (FAAH): discovery of phosphorylcholine derivatives of N-acyl ethanolamines. Biochemistry 45:11267–11277.

    Article  PubMed  CAS  Google Scholar 

  • Naidu PS, Varvel SA, Ahn K, Cravatt BF, Martin BR, Lichtman AH (2007) Evaluation of fatty acid amide hydrolase inhibition in murine models of emotionality. Psychopharmacology 192:61–70.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Oddi S, Bari M, Battista N, Barsacchi D, Cozzani I, Maccarrone M (2005) Confocal microscopy and biochemical analysis reveals spatial and functional separation between anandamide uptake and hydrolysis in human keratinocytes. Cell Mol Life Sci 62:386–395.

    Article  PubMed  CAS  Google Scholar 

  • Ortega-Gutiérrez S, Hawkins EG, Viso A, López-Rodríguez ML, Cravatt BF (2004) Comparison of anandamide transport in FAAH wild-type and knockout neurons: evidence for contributions by both FAAH and the CB1 receptor to anandamide uptake. Biochemistry 43:8184–8190.

    Article  PubMed  CAS  Google Scholar 

  • Overton HA, Babbs AJ, Doel SM, Fyfe MCT, Gardner LS, Griffin G, Jackson HC, Procter MJ, Rasamison CM, Tang-Christensen M, Widdowson PS, Williams GM, Reynet C (2006) Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab 3:167–175.

    Article  PubMed  CAS  Google Scholar 

  • Palomäki VA, Lehtonen M, Savinainen JR, Laitinen JT (2007) Visualization of 2-arachidonoylglycerol accumulation and cannabinoid CB1 receptor activity in rat brain cryosections by functional autoradiography. J Neurochem 101:972–981.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Ramakrishnan M, Kenoth R, Kamlekar RK, Chandra MS, Radhakrishnan TP, Swamy MJ (2002) N-Myristoylethanolamine-cholesterol (1:1) complex: first evidence from differential scanning calorimetry, fast-atom-bombardment mass spectrometry and computational modelling. FEBS Lett 531:343–347.

    Article  PubMed  CAS  Google Scholar 

  • Rockwell CE, Kaminski NE (2004) A cyclooxygenase metabolite of anandamide causes inhihbition of interleukin-2 secretion in murine splenocytes. J Pharmacol Exp Ther 311:683–690.

    Article  PubMed  CAS  Google Scholar 

  • Ross RA, Craib SJ, Stevenson LA, Pertwee RG, Henderson A, Toole J, Ellington HC (2002) Pharmacological characterization of the anandamide cyclooxygenase metabolite: prostaglandin E2 ethanolamide. J Pharmacol Exp Ther 301:900–907.

    Article  PubMed  CAS  Google Scholar 

  • Saghatelian A, McKinney MK, Bandell M, Patapoutian A, Cravatt BF (2006) A FAAH-regulated class of N-acyl taurines that activates TRP ion channels. Biochemistry 45:9008–9015.

    Article  CAS  Google Scholar 

  • Sang N, Zhang J, Chen C (2006) PGE2 glycerol ester, a COX-2 oxidative metabolite of 2-arachidonoyl glycerol, modulates inhibitory synaptic transmission in mouse hippocampal neurons. J Physiol 572:735–745.

    PubMed  CAS  Google Scholar 

  • Schmid PC, Zuzarte-Augustin ML, Schmid HHO (1985) Properties of rat liver N-acylethanolamine amidohydrolase. J Biol Chem 260:14145–14149.

    PubMed  CAS  Google Scholar 

  • Simpson CMF, Itabe H, Reynolds CN, King WC, Glomset JA (1991) Swiss 3T3 cells preferentially incorporate sn-2-arachidonoyl monoacylglycerol into sn-1-stearoyl-2-arachidonoyl phosphatidylinositol. J Biol Chem 266:15902–15909.

    PubMed  CAS  Google Scholar 

  • Sipe JC, Chiang K, Gerber AL, Beutler Em Cravatt BF (2002) A missense mutation in human fatty acid amide hydrolase associated with problem drug use. Proc Natl Acad Sci USA 99:8394–8399.

    Article  PubMed  CAS  Google Scholar 

  • Sipe JC, Waalen J, Gerber A, Beutler E (2005) Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH). Int J Obesity 29:755–759.

    Article  CAS  Google Scholar 

  • Solinas M, Justinova Z, Goldberg SR, Tanda G (2006) Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats. J Neurochem 98:408–419.

    Article  PubMed  CAS  Google Scholar 

  • Thors L, Fowler CJ (2006) Is there a temperature-dependent uptake of anandamide into cells? Br J Pharmacol 149:173–181.

    Article  CAS  Google Scholar 

  • Thors L, Alajakku K, Fowler CJ (2007) The “specific” tyrosine kinase inhibitor genistein inhibits the enzymic hydrolysis of anandamide. Implications for anandamide uptake. Br J Pharmacol 150:951–960.

    Article  PubMed  CAS  Google Scholar 

  • Ueda N, Yamanaka K, Yamamoto S (2001) Purification and characterization of an acid amidase selective for N-palmitoylethanolamine, a putative endogenous anti-inflammatory substance. J Biol Chem 276:35552–35557.

    Article  PubMed  CAS  Google Scholar 

  • Vandevoorde S, Jonsson K-O, Labar G, Persson E, Lambert DM, Fowler CJ (2007) Lack of selectivity of URB602 for 2-oleoylglycerol compared to anandamide hydrolysis in vitro. Br J Pharmacol 150:186–191.

    Article  PubMed  CAS  Google Scholar 

  • van Tienhoven M, Atkins J, Li Y, Glynn P (2002) Human neuropathy target esterase catalyzes hydrolysis of membrane lipids. J Biol Chem 277:20942–20948.

    Article  PubMed  CAS  Google Scholar 

  • Varvel SA, Cravatt BF, Engram AE, Lichtman AH (2006) Fatty acid amide hydrolase (–/–) mice exhibit an increased sensitivity to the disruptive effects of anandamide or oleamide in a working memory water maze task. J Pharmacol Exp Ther 317:251–257.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Wang H, Xie H, Guo Y, Zhang H, Takahashi T, Kingsley PJ, Marnett LJ, Das SK, Cravatt BF, Dey SK (2006a) Fatty acid amide hydrolase deficiency limits early pregnancy events. J Clin Invest 116:2122–2131.

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Ramirez F, Krishnamurthy G, Gilbert A, Kadakia N, Xu J, Kalgaonkar G, Ramarao MK, Edris W, Rogers KE, Jones PG (2006b) High-throughput screening for the discovery of inhibitors of fatty acid amide hydrolase using a microsome-based fluorescent assay. J Biomol Screen 11:519–527.

    Article  PubMed  CAS  Google Scholar 

  • Weber A, Ni J, Ling K-HJ, Acheampong A, Tang-Liu DD-S, Burk R, Cravatt BF, Woodward D (2004) Formation of prostamides from anandamide in FAAH knockout mice analyzed by HPLC with tandem mass spectrometry. J Lipid Res 45:757–763.

    Article  PubMed  CAS  Google Scholar 

  • 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 281:36569–36578.

    Article  PubMed  CAS  Google Scholar 

  • Wise LE, Shelton CC, Cravatt BF, Martin BR, Lichtman AH (2007) Assessment of anandamide’s pharmacological effects in mice deficient of both fatty acid amide hydrolase and cannabinoid CB1 receptors. Eur J Pharmacol 557:44–48.

    Article  PubMed  CAS  Google Scholar 

  • Woodward DF, Krauss AH, Wang JW, Protzman CE, Nieves AL, Liang Y, Donde Y, Burk RM, Landsverk K, Struble C (2007) Identification of an antagonist that selectively blocks the activity of prostamides (prostaglandin-ethanolamides) in the feline iris. Br J Pharmacol 150:342–352.

    Article  PubMed  CAS  Google Scholar 

  • Zhang D, Saraf A, Kolasa T, Bhatia P, Zheng GZ, Patel M, Lannoye GS, Richardson P, Stewart A, Rogers JC, Brioni JD, Surowy CS (2007) Fatty acid amide hydrolase inhibitors display broad selectivity and inhibit multiple carboxylesterases as off-targets. Neuropharmacology 52:1095–1105.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Clinical Neuroscience, Umeå University, SE901 87, Umeå, Sweden

    Christopher J. Fowler

Authors
  1. Christopher J. Fowler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lina Thors
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Center for Neurosciences of Coimbra, University of Coimbra, Coimbra, 3000-045, Portugal

    Attila Köfalvi (Faculty of Medicine) (Faculty of Medicine)

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer

About this chapter

Cite this chapter

Fowler, C.J., Thors, L. (2008). Removal of Endocannabinoids by the Body: Mechanisms and Therapeutic Possibilities. In: Köfalvi, A. (eds) Cannabinoids and the Brain. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-74349-3_3

Download citation

Publish with us

Policies and ethics

Search

Navigation