Abstract
Marijuana is a common name for the plant Cannabis sativa, whose intoxicating and medicinal effects have been known for thousand of years. The active principle of marijuana, (−)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), exerts its pharmacological effects by binding to selective receptors present on the membranes of neurons and other cells. These cannabinoid receptors are normally engaged by a family of lipid mediators, called endocannabinoids, which are thought to participate in the regulation of a diversity of brain functions, including pain, mood, appetite and memory.
The endocannabinoid system is comprised of the endocannabinoids, mainly anandamide (arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG), proteins that control their formation and deactivation, and cell-surface receptors (CB1 and CB2) that transduce their actions. The key components of endocannabinoid signaling are found in the brain and spinal cord, but also in many peripheral organs and tissues.
In this chapter, we outline current views on how endocannabinoid substances are produced, act on cannabinoid receptors, and are deactivated in the brain. In addition, we review recent progress on the development of pharmacological agents that interfere with endocannabinoid deactivation and discuss their potential utility in the treatment of cannabinoid-based therapeutics.
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Adamczyk P, McCreary AC, Przegalinski E, Mierzejewski P, Bienkowski P, Filip M (2009) The effects of fatty acid amide hydrolase inhibitors on maintenance of cocaine and food self-administration and on reinstatement of cocaine-seeking and food-taking behavior in rats. J Physiol Pharmacol 60(3):119–125
Adams R (1942) Marihuana: Harvey lecture, February 19, 1942. Bull N Y Acad Med 18(11):705–730
Agarwal N, Pacher P, Tegeder I, Amaya F, Constantin CE, Brenner GJ, Rubino T, Michalski CW, Marsicano G, Monory K, Mackie K, Marian C, Batkai S, Parolaro D, Fischer MJ, Reeh P, Kunos G, Kress M, Lutz B, Woolf CJ, Kuner R (2007) Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat Neurosci 10(7):870–879
Aggarwal SK, Carter GT, Sullivan MD, ZumBrunnen C, Morrill R, Mayer JD (2009) Medicinal use of cannabis in the United States: historical perspectives, current trends, and future directions. J Opioid Manag 5(3):153–168
Allen AC, Gammon CM, Ousley AH, McCarthy KD, Morell P (1992) Bradykinin stimulates arachidonic acid release through the sequential actions of an sn-1 diacylglycerol lipase and a monoacylglycerol lipase. J Neurochem 58(3):1130–1139
Anand P, Whiteside G, Fowler CJ, Hohmann AG (2009) Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain Res Rev 60(1):255–266, Review
Andreasson S, Allebeck P, Engstrom A, Rydberg U (1987) Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet 2:1483–1486
Bell RL, Kennerly DA, Stanford N, Majerus PW (1979) Diglyceride lipase: a pathway for arachidonate release from human platelets. Proc Natl Acad Sci U S A 76(7):3238–3241
Beltramo M, Piomelli D (2000) Carrier-mediated transport and enzymatic hydrolysis of the endogenous cannabinoid 2-arachidonylglycerol. Neuroreport 11(6):1231–1235
Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D (1997) Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277(5329):1094–1097
Bennett CF, Balcarek JM, Varrichio A, Crooke ST (1988) Molecular cloning and complete amino-acid sequence of form-I phosphoinositide-specific phospholipase C. Nature 334(6179):268–270
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(Pt 3):817–824
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(3):463–468
Blankman JL, Simon GM, Cravatt BF (2007) A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol 14(12):1347–1356
Blankman JL, Long JZ, Trauger SA, Siuzdak G, Cravatt BF (2013) ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC. Proc Natl Acad Sci U S A 110(4):1500–1505
Bluett RJ, Gamble-George JC, Hermanson DJ, Hartley ND, Marnett LJ, Patel S (2014) Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation. Transl Psychiatry 4, e408
Boggs DL, Kelly DL, McMahon RP, Gold JM, Gorelick DA, Linthicum J, Conley RR, Liu F, Waltz J, Huestis MA, Buchanan RW (2012) Rimonabant for neurocognition in schizophrenia: a 16-week double blind randomized placebo controlled trial. Schizophr Res 134(2–3):207–210
Bortolato M, Mangieri RA, Fu J, Kim JH, Arguello O, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2007) Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress. Biol Psychiatry 62(10):1103–1110
Busquets-Garcia A, Puighermanal E, Pastor A, de la Torre R, Maldonado R, Ozaita A (2011) Differential role of anandamide and 2-arachidonoylglycerol in memory and anxiety-like responses. Biol Psychiatry 70(5):479–486
Cadas H, Gaillet S, Beltramo M, Venance L, Piomelli D (1996) Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by calcium and cAMP. J Neurosci 16(12):3934–3942
Cadas H, di Tomaso E, Piomelli D (1997) Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J Neurosci 17(4):1226–1242
Cahill K, Stevens S, Perera R, Lancaster T (2013) Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev 5, CD009329, Review
Calignano A, La Rana G, Giuffrida A, Piomelli D (1998) Control of pain initiation by endogenous cannabinoids. Nature 394(6690):277–281
Castane A, Valjent E, Ledent C, Parmentier M, Maldonado R, Valverde O (2002) Lack of CB1 cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence. Neuropharmacology 43:857–867
Castillo PE, Younts TJ, Chávez AE, Hashimotodani Y (2012) Endocannabinoid signaling and synaptic function. Neuron 76(1):70–81, Review
Chevaleyre V, Takahashi KA, Castillo PE (2006) Endocannabinoid-mediated synaptic plasticity in the CNS. Annu Rev Neurosci 29:37–76, Review
Clapper JR, Mangieri RA, Piomelli D (2009) The endocannabinoid system as a target for the treatment of cannabis dependence. Neuropharmacology 56(Suppl 1):235–243, Review
Clapper JR, Moreno-Sanz G, Russo R, Guijarro A, Vacondio F, Duranti A, Tontini A, Sanchini S, Sciolino NR, Spradley JM, Hohmann AG, Calignano A, Mor M, Tarzia G, Piomelli D (2010) Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat Neurosci 13(10):1265–1270
Cohen C, Perrault G, Voltz C, Steinberg R, Soubrie P (2002) SR141716, a central cannabinoid (CB(1)) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats. Behav Pharmacol 13:451–463
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(6604):83–87
Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci U S A 98(16):9371–9376
Dennis EA, Deems RA, Harkewicz R, Quehenberger O, Brown HA, Milne SB, Myers DS, Glass CK, Hardiman G, Reichart D, Merrill AH Jr, Sullards MC, Wang E, Murphy RC, Raetz CR, Garrett TA, Guan Z, Ryan AC, Russell DW, McDonald JG, Thompson BM, Shaw WA, Sud M, Zhao Y, Gupta S, Maurya MR, Fahy E, Subramaniam S (2010) A mouse macrophage lipidome. J Biol Chem 285(51):39976–39985
Desarnaud F, Cadas H, Piomelli D (1995) Anandamide amidohydrolase activity in rat brain microsomes. Identification and partial characterization. J Biol Chem 270(11):6030–6035
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(5):605–613
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(5090):1946–1949
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(6507):686–691
Díaz-Laviada I (2011) The endocannabinoid system in prostate cancer. Nat Rev Urol 8(10):553–561, Review
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(16):10819–10824
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(5):1260–1264
DiPatrizio NV, Piomelli D (2012) The thrifty lipids: endocannabinoids and the neural control of energy conservation. Trends Neurosci 35(7):403–411, Review
DiPatrizio NV, Piomelli D (2015) Intestinal lipid-derived signals that sense dietary fat. J Clin Invest 125(3):891–898, Review
Dlugos A, Childs E, Stuhr KL, Hillard CJ, de Wit H (2012) Acute stress increases circulating anandamide and other N-acylethanolamines in healthy humans. Neuropsychopharmacology 37(11):2416–2427
Dziadulewicz EK, Bevan SJ, Brain CT, Coote PR, Culshaw AJ, Davis AJ, Edwards LJ, Fisher AJ, Fox AJ, Gentry C, Groarke A, Hart TW, Huber W, James IF, Kesingland A, La Vecchia L, Loong Y, Lyothier I, McNair K, O’Farrell C, Peacock M, Portmann R, Schopfer U, Yaqoob M, Zadrobilek J (2007) Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone: a potent, orally bioavailable human CB1/CB2 dual agonist with antihyperalgesic properties and restricted central nervous system penetration. J Med Chem 50(16):3851–3856
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(1410):2081–2085
Egertová M, Cravatt BF, Elphick MR (2003) Comparative analysis of fatty acid amide hydrolase and cb(1) cannabinoid receptor expression in the mouse brain: evidence of a widespread role for fatty acid amide hydrolase in regulation of endocannabinoid signaling. Neuroscience 119(2):481–496
Engeli S (2012) Central and peripheral cannabinoid receptors as therapeutic targets in the control of food intake and body weight. Handb Exp Pharmacol 209:357–381, Review
Farooqui AA, Horrocks LA, Farooqui T (2000) Deacylation and reacylation of neural membrane glycerophospholipids. J Mol Neurosci 14(3):123–135, Review
Flygare J, Sander B (2008) The endocannabinoid system in cancer-potential therapeutic target? Semin Cancer Biol 18(3):176–189, Review
Fowler CJ, Gustafsson SB, Chung SC, Persson E, Jacobsson SO, Bergh A (2010) Targeting the endocannabinoid system for the treatment of cancer--a practical view. Curr Top Med Chem 10(8):814–827, Review
Freimuth N, Ramer R, Hinz B (2010) Antitumorigenic effects of cannabinoids beyond apoptosis. J Pharmacol Exp Ther 332(2):336–344, Review
Freund TF, Katona I, Piomelli D (2003) Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83(3):1017–1066, Review
Fu J, Gaetani S, Oveisi F, Lo Verme J, Serrano A, Rodríguez De Fonseca F, Rosengarth A, Luecke H, Di Giacomo B, Tarzia G, Piomelli D (2003) Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 425(6953):90–3
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 (2011) A catalytically silent FAAH-1 variant drives anandamide transport in neurons. Nat Neurosci 15(1):64–69
Gaoni Y, Mechoulam R (1964) Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 86:1646–1647
Giuffrida A, Parsons LH, Kerr TM, Rodríguez de Fonseca F, Navarro M, Piomelli D (1999) Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat Neurosci 2(4):358–363
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 U S A 102(51):18620–18625
González S, Cebeira M, Fernández-Ruiz J (2005) Cannabinoid tolerance and dependence: a review of studies in laboratory animals. Pharmacol Biochem Behav 81(2):300–318, Review
Greco R, Bandiera T, Mangione A, Demartini C, Siani F, Nappi G, Sandrini G, Guijarro A, Armirotti A, Piomelli D, Tassorelli C (2015) Effects of peripheral FAAH blockade on NTG-induced hyperalgesia-evaluation of URB937 in an animal model of migraine. Cephalalgia 35(12):1065–1076
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(2):441–458
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(7):3662–3665
Harizi H, Corcuff JB, Gualde N (2008) Arachidonic-acid-derived eicosanoids: roles in biology and immunopathology. Trends Mol Med 14(10):461–469, Review
Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 87(5):1932–1936
Hillard CJ, Wilkison DM, Edgemond WS, Campbell WB (1995) Characterization of the kinetics and distribution of N-arachidonylethanolamine (anandamide) hydrolysis by rat brain. Biochim Biophys Acta 1257(3):249–256
Hirvonen J, Goodwin RS, Li CT, Terry GE, Zoghbi SS, Morse C, Pike VW, Volkow ND, Huestis MA, Innis RB (2012) Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol Psychiatry 17(6):642–649
Hohmann AG, Farthing JN, Zvonok AM, Makriyannis A (2004) Selective activation of cannabinoid CB2 receptors suppresses hyperalgesia evoked by intradermal capsaicin. J Pharmacol Exp Ther 308:446–453
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(7045):1108–1112
Ibrahim MM, Deng H, Zvonok A, Cockayne DA, Kwan J et al (2003) Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci U S A 100:10529–10533
Iversen LL (2000) The science of marijuana. Oxford University Press, Oxford
Iversen L (2001) Cannabinoids in pain management. Few well controlled trials of cannabis exist for systemic review. BMJ 323(7323):1250
Jung KM, Mangieri R, Stapleton C, Kim J, Fegley D, Wallace M, Mackie K, Piomelli D (2005) Stimulation of endocannabinoid formation in brain slice cultures through activation of group I metabotropic glutamate receptors. Mol Pharmacol 68(5):1196–1202
Jung KM, Astarita G, Zhu C, Wallace M, Mackie K, Piomelli D (2007) A key role for diacylglycerol lipase-alpha in metabotropic glutamate receptor-dependent endocannabinoid mobilization. Mol Pharmacol 72(3):612–621
Jung KM, Clapper JR, Fu J, D’Agostino G, Guijarro A, Thongkham D, Avanesian A, Astarita G, DiPatrizio NV, Frontini A, Cinti S, Diano S, Piomelli D (2012a) 2-arachidonoylglycerol signaling in forebrain regulates systemic energy metabolism. Cell Metab 15(3):299–310
Jung KM, Sepers M, Henstridge CM, Lassalle O, Neuhofer D, Martin H, Ginger M, Frick A, DiPatrizio NV, Mackie K, Katona I, Piomelli D, Manzoni OJ (2012b) Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nat Commun 3:1080
Justinova Z, Mangieri RA, Bortolato M, Chefer SI, Mukhin AG, Clapper JR, King AR, Redhi GH, Yasar S, Piomelli D, Goldberg SR (2008) Fatty acid amide hydrolase inhibition heightens anandamide signaling without producing reinforcing effects in primates. Biol Psychiatry 64(11):930–937
Justinova Z, Panlilio LV, Moreno-Sanz G, Redhi GH, Auber A, Secci ME, Mascia P, Bandiera T, Armirotti A, Bertorelli R, Chefer SI, Barnes C, Yasar S, Piomelli D, Goldberg SR (2015) Effects of fatty acid amide hydrolase (FAAH) inhibitors in non-human primate models of nicotine reward and relapse. Neuropsychopharmacology 40(9):2185–2197
Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M (2009) Endocannabinoid-mediated control of synaptic transmission. Physiol Rev 89(1):309–380, Review
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(43):27218–27223
Karsak M, Cohen-Solal M, Freudenberg J, Ostertag A, Morieux C, Kornak U, Essig J, Erxlebe E, Bab I, Kubisch C, de Vernejoul MC, Zimmer A (2005) Cannabinoid receptor type 2 gene is associated with human osteoporosis. Hum Mol Genet 14(22):3389–3396
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(1):76–81
Katona I, Freund TF (2012) Multiple functions of endocannabinoid signaling in the brain. Annu Rev Neurosci 35:529–558, Review
Katona I, Sperlágh B, Sík A, Käfalvi A, Vizi ES, Mackie K, Freund TF (1999) Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci 19(11):4544–4558
Katona I, Urbán GM, Wallace M, Ledent C, Jung KM, Piomelli D, Mackie K, Freund TF (2006) Molecular composition of the endocannabinoid system at glutamatergic synapses. J Neurosci 26(21):5628–5637
Kempe K, Hsu FF, Bohrer A, Turk J (1996) Isotope dilution mass spectrometric measurements indicate that arachidonylethanolamide, the proposed endogenous ligand of the cannabinoid receptor, accumulates in rat brain tissue post mortem but is contained at low levels in or is absent from fresh tissue. J Biol Chem 271(29):17287–17295
Kim J, Alger BE (2004) Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in hippocampus. Nat Neurosci 7(7):697–698
Kinsey SG, Nomura DK, O’Neal ST, Long JZ, Mahadevan A, Cravatt BF, Grider JR, Lichtman AH (2011) Inhibition of monoacylglycerol lipase attenuates nonsteroidal anti-inflammatory drug-induced gastric hemorrhages in mice. J Pharmacol Exp Ther 338(3):795–802
Kinsey SG, Wise LE, Ramesh D, Abdullah R, Selley DE, Cravatt BF, Lichtman AH (2013) Repeated low-dose administration of the monoacylglycerol lipase inhibitor JZL184 retains cannabinoid receptor type 1-mediated antinociceptive and gastroprotective effects. J Pharmacol Exp Ther 345(3):492–501
Koethe D, Giuffrida A, Schreiber D, Hellmich M, Schultze-Lutter F, Ruhrmann S, Klosterkötter J, Piomelli D, Leweke FM (2009) Anandamide elevation in cerebrospinal fluid in initial prodromal states of psychosis. Br J Psychiatry 194(4):371–372
Kozak KR, Rowlinson SW, Marnett LJ (2000) Oxygenation of the endocannabinoid, 2-arachidonylglycerol, to glyceryl prostaglandins by cyclooxygenase-2. J Biol Chem 275(43):33744–33749
Leweke FM, Giuffrida A, Koethe D, Schreiber D, Nolden BM, Kranaster L, Neatby MA, Schneider M, Gerth CW, Hellmich M, Klosterkötter J, Piomelli D (2007) Anandamide levels in cerebrospinal fluid of first-episode schizophrenic patients: impact of cannabis use. Schizophr Res 94(1–3):29–36
Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, Klosterkötter J, Hellmich M, Koethe D (2012) Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2, e94
Li CM, Hong SB, Kopal G, He X, Linke T, Hou WS, Koch J, Gatt S, Sandhoff K, Schuchman EH (1998) Cloning and characterization of the full-length cDNA and genomic sequences encoding murine acid ceramidase. Genomics 50(2):267–274
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(36):13345–13350
Lourenço J, Matias I, Marsicano G, Mulle C (2011) Pharmacological activation of kainate receptors drives endocannabinoid mobilization. J Neurosci 31(9):3243–3248
LoVerme J, La Rana G, Russo R, Calignano A, Piomelli D (2005) The search for the palmitoylethanolamide receptor. Life Sci 77(14):1685–1698, Review
Mackie K (2006) Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol 46:101–122, Review
Magotti P, Bauer I, Igarashi M, Babagoli M, Marotta R, Piomelli D, Garau G (2015) Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: regulation of fatty acid ethanolamide biosynthesis by bile acids. Structure 23(3):598–604
Maldonado R, Valverde O, Berrendero F (2006) Involvement of the endocannabinoid system in drug addiction. Trends Neurosci 29:225–232, Review
Malfitano AM, Ciaglia E, Gangemi G, Gazzerro P, Laezza C, Bifulco M (2011) Update on the endocannabinoid system as an anticancer target. Expert Opin Ther Targets 15(3):297–308, Review
Marrs WR, Blankman JL, Horne EA, Thomazeau A, Lin YH, Coy J, Bodor AL, Muccioli GG, Hu SS, Woodruff G, Fung S, Lafourcade M, Alexander JP, Long JZ, Li W, Xu C, Möller T, Mackie K, Manzoni OJ, Cravatt BF, Stella N (2010) The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nat Neurosci 13(8):951–957
Marsicano G, Lutz B (1999) Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci 11(12):4213–4225
Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346(6284):561–564
Mátyás F, Urbán GM, Watanabe M, Mackie K, Zimmer A, Freund TF, Katona I (2008) Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area. Neuropharmacology 54(1):95–107
McKinney MK, Cravatt BF (2005) Structure and function of fatty acid amide hydrolase. Annu Rev Biochem 74:411–432, Review
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(1):83–90
Meltzer HY, Arvanitis L, Bauer D, Rein W, Meta-Trial Study Group (2004) Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry 161(6):975–984
Moreno-Sanz G, Barrera B, Guijarro A, d’Elia I, Otero JA, Alvarez AI, Bandiera T, Merino G, Piomelli D (2011) The ABC membrane transporter ABCG2 prevents access of FAAH inhibitor URB937 to the central nervous system. Pharmacol Res 64(4):359–363
Moreno-Sanz G, Sasso O, Guijarro A, Oluyemi O, Bertorelli R, Reggiani A, Piomelli D (2012) Pharmacological characterization of the peripheral FAAH inhibitor URB937 in female rodents: interaction with the Abcg2 transporter in the blood-placenta barrier. Br J Pharmacol 167(8):1620–1628
Moreno-Sanz G, Duranti A, Melzig L, Fiorelli C, Ruda GF, Colombano G, Mestichelli P, Sanchini S, Tontini A, Mor M, Bandiera T, Scarpelli R, Tarzia G, Piomelli D (2013) Synthesis and structure-activity relationship studies of O-biphenyl-3-yl carbamates as peripherally restricted fatty acid amide hydrolase inhibitors. J Med Chem 56(14):5917–5930
Moreno-Sanz G, Barrera B, Armirotti A, Bertozzi SM, Scarpelli R, Bandiera T, Prieto JG, Duranti A, Tarzia G, Merino G, Piomelli D (2014) Structural determinants of peripheral O-arylcarbamate FAAH inhibitors render them dual substrates for Abcb1 and Abcg2 and restrict their access to the brain. Pharmacol Res 87:87–93
Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365(6441):61–65
Munson AE, Harris LS, Friedman MA, Dewey WL, Carchman RA (1975) Antineoplastic activity of cannabinoids. J Natl Cancer Inst 55(3):597–602
Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF (2010) Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140(1):49–61
Nyilas R, Gregg LC, Mackie K, Watanabe M, Zimmer A, Hohmann AG, Katona I (2009) Molecular architecture of endocannabinoid signaling at nociceptive synapses mediating analgesia. Eur J Neurosci 29(10):1964–1978
Orio L, Edwards S, George O, Parsons LH, Koob GF (2009) A role for the endocannabinoid system in the increased motivation for cocaine in extended-access conditions. J Neurosci 29:4846–4857
Panlilio LV, Justinova Z, Goldberg SR (2013) Inhibition of FAAH and activation of PPAR: new approaches to the treatment of cognitive dysfunction and drug addiction. Pharmacol Ther 138(1):84–102, Review
Park JH, Schuchman EH (2006) Acid ceramidase and human disease. Biochim Biophys Acta 1758(12):2133–2138, Review
Pertwee RG (2012) Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci 367(1607):3353–3363, Review
Pete MJ, Ross AH, Exton JH (1994) Purification and properties of phospholipase A1 from bovine brain. J Biol Chem 269(30):19494–19500
Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4(11):873–884, Review. No abstract available
Piomelli D (2014) More surprises lying ahead. The endocannabinoids keep us guessing. Neuropharmacology 76 Pt B:228–34 (Review)
Piomelli D, Sasso O (2014) Peripheral gating of pain signals by endogenous lipid mediators. Nat Neurosci 17(2):164–174, Review
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 U S A 96(10):5802–5807
Piomelli D, Astarita G, Rapaka R (2007) A neuroscientist’s guide to lipidomics. Nat Rev Neurosci 8(10):743–754, Review
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(3):1020–1024
Realini N, Solorzano C, Pagliuca C, Pizzirani D, Armirotti A, Luciani R, Costi MP, Bandiera T, Piomelli D (2013) Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity. Sci Rep 3:1035
Russo EB (2007) History of cannabis and its preparations in saga, science, and sobriquet. Chem Biodivers 4(8):1614–1648
Sarfaraz S, Adhami VM, Syed DN, Afaq F, Mukhtar H (2008) Cannabinoids for cancer treatment: progress and promise. Cancer Res 68(2):339–342, Review
Sasso O, Bertorelli R, Bandiera T, Scarpelli R, Colombano G, Armirotti A, Moreno-Sanz G, Reggiani A, Piomelli D (2012) Peripheral FAAH inhibition causes profound antinociception and protects against indomethacin-induced gastric lesions. Pharmacol Res 65(5):553–563
Sasso O, Moreno-Sanz G, Martucci C, Realini N, Dionisi M, Mengatto L, Duranti A, Tarozzo G, Tarzia G, Mor M, Bertorelli R, Reggiani A, Piomelli D (2013) Antinociceptive effects of the N-acylethanolamine acid amidase inhibitor ARN077 in rodent pain models. Pain 154(3):350–360
Schlosburg JE, Carlson BL, Ramesh D, Abdullah RA, Long JZ, Cravatt BF, Lichtman AH (2009) Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice. AAPS J 11(2):342–352
Schmid PC, Krebsbach RJ, Perry SR, Dettmer TM, Maasson JL, Schmid HH (1995) Occurrence and postmortem generation of anandamide and other long-chain N-acylethanolamines in mammalian brain. FEBS Lett 375(1–2):117–120
Sciolino NR, Zhou W, Hohmann AG (2011) Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats. Pharmacol Res 64(3):226–234
Shulga YV, Topham MK, Epand RM (2011) Regulation and functions of diacylglycerol kinases. Chem Rev 111(10):6186–6208, Review
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(36):26465–26472
Simon GM, Cravatt BF (2008) Anandamide biosynthesis catalyzed by the phosphodiesterase GDE1 and detection of glycerophospho-N-acyl ethanolamine precursors in mouse brain. J Biol Chem 283(14):9341–9349
Soria G, Mendizábal V, Touriño C, Robledo P, Ledent C, Parmentier M, Maldonado R, Valverde O (2005) Lack of CB1 cannabinoid receptor impairs cocaine self-administration. Neuropsychopharmacology 30:1670–1680
Starowicz K, Makuch W, Korostynski M, Malek N, Slezak M, Zychowska M, Petrosino S, De Petrocellis L, Cristino L, Przewlocka B, Di Marzo V (2013) Full inhibition of spinal FAAH leads to TRPV1-mediated analgesic effects in neuropathic rats and possible lipoxygenase-mediated remodeling of anandamide metabolism. PLoS One 8(4), e60040
Steffens M, Feuerstein TJ, van Velthoven V, Schnierle P, Knörle R (2003) Quantitative measurement of depolarization-induced anandamide release in human and rat neocortex. Naunyn Schmiedebergs Arch Pharmacol 368(5):432–436
Stein C, Zöllner C (2009) Opioids and sensory nerves. Handb Exp Pharmacol 194:495–518, Review
Stella N, Piomelli D (2001) Receptor-dependent formation of endogenous cannabinoids in cortical neurons. Eur J Pharmacol 425(3):189–196
Stella N, Schweitzer P, Piomelli D (1997) A second endogenous cannabinoid that modulates long-term potentiation. Nature 388(6644):773–778
Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215(1):89–97
Tam J, Vemuri VK, Liu J, Bátkai S, Mukhopadhyay B, Godlewski G, Osei-Hyiaman D, Ohnuma S, Ambudkar SV, Pickel J, Makriyannis A, Kunos G (2010) Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest 120(8):2953–2966
Thanos PK, Dimitrakakis ES, Rice O, Gifford A, Volkow ND (2005) Ethanol self-administration and ethanol conditioned place preference are reduced in mice lacking cannabinoid CB1 receptors. Behav Brain Res 164(2):206–213
Thomas EA, Cravatt BF, Danielson PE, Gilula NB, Sutcliffe JG (1997) Fatty acid amide hydrolase, the degradative enzyme for anandamide and oleamide, has selective distribution in neurons within the rat central nervous system. J Neurosci Res 50(6):1047–1052
Ueda N, Kurahashi Y, Yamamoto S, Tokunaga T (1995a) Partial purification and characterization of the porcine brain enzyme hydrolyzing and synthesizing anandamide. J Biol Chem 270(40):23823–7
Ueda N, Yamamoto K, Yamamoto S, Tokunaga T, Shirakawa E, Shinkai H, Ogawa M, Sato T, Kudo I, Inoue K et al (1995b) Lipoxygenase-catalyzed oxygenation of arachidonylethanolamide, a cannabinoid receptor agonist. Biochim Biophys Acta 1254(2):127–34
Ueda N, Tsuboi K, Uyama T (2010) N-acylethanolamine metabolism with special reference to N-acylethanolamine-hydrolyzing acid amidase (NAAA). Prog Lipid Res 49(4):299–315, Review
Ueda N, Tsuboi K, Uyama T (2013) Metabolism of endocannabinoids and related N-acylethanolamines: canonical and alternative pathways. FEBS J 280(9):1874–1894, Review
van der Stelt M, Di Marzo V (2003) The endocannabinoid system in the basal ganglia and in the mesolimbic reward system: implications for neurological and psychiatric disorders. Eur J Pharmacol 480(1–3):133–150, Review
Velasco G, Galve-Roperh I, Sánchez C, Blázquez C, Guzmán M (2004) Hypothesis: cannabinoid therapy for the treatment of gliomas? Neuropharmacology 47(3):315–323, Review
Wei D, Piomelli D (2015) Cannabinoid-based drugs: potential applications in addiction and other mental disorders. FOCUS 13(3):307–316, Review
Wells DL, Ott CA (2011) The “new” marijuana. Ann Pharmacother 45(3):414–417, Review
Wollner HJ, Matchett JR, Levine J, Loewe S (1942) Isolation of a Physiologically Active Tetrahydrocannabinol from Cannabis Sativa Resin. J Am Chem Soc 64(1):26–29
Wong DF, Kuwabara H, Horti AG, Raymont V, Brasic J, Guevara M, Ye W, Dannals RF, Ravert HT, Nandi A, Rahmim A, Ming JE, Grachev I, Roy C, Cascella N (2010) Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR. Neuroimage 52(4):1505–1513
Woodward DF, Carling RW, Cornell CL, Fliri HG, Martos JL, Pettit SN, Liang Y, Wang JW (2008) The pharmacology and therapeutic relevance of endocannabinoid derived cyclo-oxygenase (COX)-2 products. Pharmacol Ther 120(1):71–80, Review
Xi ZX, Peng XQ, Li X, Song R, Zhang HY, Liu QR, Yang HJ, Bi GH, Li J, Gardner EL (2011) Brain cannabinoid CB2 receptors modulate cocaine’s actions in mice. Nat Neurosci 14(9):1160–1166
Ye L, Zhang B, Seviour EG, Tao KX, Liu XH, Ling Y, Chen JY, Wang GB (2011) Monoacylglycerol lipase (MAGL) knockdown inhibits tumor cells growth in colorectal cancer. Cancer Lett 307(1):6–17
Zhu C, Solorzano C, Sahar S, Realini N, Fung E, Sassone-Corsi P, Piomelli D (2011) Proinflammatory stimuli control N-acylphosphatidylethanolamine-specific phospholipase D expression in macrophages. Mol Pharmacol 79(4):786–792
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Jung, KM., Piomelli, D. (2015). Cannabinoids and Endocannabinoids. In: Pfaff, D., Volkow, N. (eds) Neuroscience in the 21st Century. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6434-1_136-1
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DOI: https://doi.org/10.1007/978-1-4614-6434-1_136-1