Neuromodulatory Actions of Endocannabinoids in Pain and Sedation

  • Luciano De Petrocellis
  • Tiziana Bisogno
  • Vincenzo Di Marzo
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 523)


Endocannabinoids1 are endogenous substances that bind to and activate at least one of the two high affinity membrane receptors discovered for marijuana’s psychoactive principle, (-)-¡õ9-tetrahydrocannabinol (THC). Three types of endocannabinoids have been described so far in both nervous and non-nervous tissues: 1) the anandamides,1 i.e. amides of ethanolamine with polyunsaturated fatty acids with at least twenty carbon atoms and three 1,4-diene double bonds, of which the C20: 4 homologue, arachi-donoylethanolamide (AEA)2,3 has been most thoroughly studied; 2) 2-arachidonoyl glycerol (2-AG)4,5; and 3) the recently described 2-arachidonyl glyceryl ether, or noladin ether,6 whose pharmacological activity as an endocannabinoid has not yet been thoroughly assessed. An entirely saturated AEA congener, palmitoylethanolamide (PEA), was proposed to act as an endocannabinoid at yet-to-be-characterized receptors, but the precise mechanism(s) underlying the THC-like anti-inflammatory and analgesic activity of this compound is(are) still a matter for speculation.7


Fatty Acid Amide Hydrolase Formalin Test Glyceryl Ether Vanilloid Receptor Fatty Acid Ethanolamides 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    V. Di Marzo, ‘Endocannabinoids’ and other fatty acid derivatives with cannabimimetic properties: biochemistry and possble physiopathological relevance, Biochim. Biophys. Acta 1392:153 (1998).PubMedCrossRefGoogle Scholar
  2. 2.
    W. A. Devane, L. Hanus, A. Breuer, R. G. Pertwee, L. A. Stevenson, G. Griffin, D. Gibson, A. Mandelbaum, A. Etinger, and R. Mechoulam, Isolation and structure of a brain constituent that binds to the cannabinoid receptor, Science 258:1946 (1992).PubMedCrossRefGoogle Scholar
  3. 3.
    L. Hanus, A. Gopher, S. Almog, and R. Mechoulam, Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor, J. Med. Chem. 36:3032 (1993).PubMedCrossRefGoogle Scholar
  4. 4.
    R. Mechoulam, S. Ben-Shabat, L. Hanus, M. Ligumsky, N. E. Kaminski, A. R. Schatz, A. Gopher, S. Almog, B. R. Martin, D. R. Compton, R. G. Pertwee, G. Griffin, M. Bayewitch, J. Barg, and Z. Vogel, Identifation of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors, Biochem. Pharmacol. 50:83 (1995).PubMedCrossRefGoogle Scholar
  5. 5.
    T. Sugiura, S. Kondo, A. Sukagawa, S. Nakane, A. Shinoda, K. Itoh, A. Yamashita, and K. Waku, 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain, Biochem. Biophys. Commun. 215:89 (1995).CrossRefGoogle Scholar
  6. 6.
    L. Hanus, S. Abu-Lafi, E. Fride, A. Breuer, Z. Vogel, D. E. Shalev, I. Kustanovich, R. Mechoulam R., 2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc. Natl. Acad. Sci. V.S.A. 98:3662 (2001).CrossRefGoogle Scholar
  7. 7.
    D. M. Lambert, and V. Di Marzo, The palmitoylethanolamide and oleamide enigmas: are these two fatty acid amides cannabimimetic? Curr. Med. Chem.; 6:757 1999.PubMedGoogle Scholar
  8. 8.
    V. Di Marzo, Biosynthesis and inactivation of endocannabinoids: relevance to their proposed role as neuromodulators. Life Sci. 65:645 (1999).PubMedCrossRefGoogle Scholar
  9. 9.
    V. Di Marzo, A. Fontana, H. Cadas, S. Schinelli, G. Cimino, J. C. Schwartz, and D. Piomelli D., Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372:686 (1994).PubMedCrossRefGoogle Scholar
  10. 10.
    G. Petersen, and H. S. Hansen, N-acylphosphatidylethanolamine-hydrolysing phospholipase D lacks the ability to transphosphatidylate. FEBS Lett. 455:41 (1999).PubMedCrossRefGoogle Scholar
  11. 11.
    N. Ueda, Q. Liu, K Yamanaka K., Marked activation of the N-acyl-phosphatidyl-ethanolamine-hydrolyzing phosphodiesterase by divalent cations. Biochim. Biophys. Acta 1532:121 (2001).PubMedCrossRefGoogle Scholar
  12. 12.
    H. H. Schmid, P. C. Schmid, V. Natarajan, 1996 The N-acylation-phosphodiesterase pathway and cell signalling. Chem. Phys. Lipids 80:133.PubMedCrossRefGoogle Scholar
  13. 13.
    V. Di Marzo, L. De Petrocellis, T. Sugiura, and Waku, Potential biosynthetic connections between the two cannabimimetic eicosanoids, anandamide and 2-arachidonoyl-glycerol, in mouse neuroblastoma cells. Biochem. Biophys. Res. Commun. 227:281 (1996).PubMedCrossRefGoogle Scholar
  14. 14.
    N. Stella, P. Schweitzer P.D. Piomelli, A second endogenous cannabinoid that modulates long-term potentiation. Nature 388:773 (1997).PubMedCrossRefGoogle Scholar
  15. 15.
    T. Bisogno, D. Melck, L. De Petrocellis, and V. Di Marzo, Phosphatidic acid as the biosynthetic precursor of the endocannabinoid 2-arachidonoylglycerol in intact mouse neuroblastoma cells stimulated with ionomycin, J. Neurochem. 72:2113 (1999).PubMedCrossRefGoogle Scholar
  16. 16.
    R. G. Pertwee, Pharmacology of cannabinoid CB1 and CB2 receptors, Pharmacol. Ther. 74:129 (1997).PubMedGoogle Scholar
  17. 17.
    M. Herkenham, A. B. Lynn, M. D. Little, M. R. Johnson, L. S. Melvin, B. R. de Costa, and K. C. Rice, Cannabinoid receptor localization in brain, Proc. Natl. Acad. Sci. U.S.A. 87:1932 (1990).PubMedCrossRefGoogle Scholar
  18. 18.
    F. Maingret, A. J. Patel, M. Lazdunski, and E. Honore, The endocannabinoid anandamide is a direct and selective blocker of the background K(+) channel TASK-1, EMBO J. 20:47 (2001).PubMedCrossRefGoogle Scholar
  19. 19.
    J. Chemin, A. Monteil, E. Perez-Reyes, J. Nargeot, and P. Lory P, Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide, EMBO J. 20:7033 (2001).PubMedCrossRefGoogle Scholar
  20. 20.
    P. M. Zygmunt, J. Petersson, D. A. Andersson, H. Chuang, M. Sorgard, V. Di Marzo, D. Julius, and E. D. Hogestatt, Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide, Nature 400:452 (1999).PubMedCrossRefGoogle Scholar
  21. 21.
    D. Smart, M. J. Gunthorpe, J. C. Jerman, S. Nasir, J. Gray, A. I. Muir, J. K. Chambers, A. D. Randall, and J. B. Davis, The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1), Br. J. Pharmacol. 129:227 (2000).PubMedCrossRefGoogle Scholar
  22. 22.
    V. Di Marzo, T. Bisogno, and L. De Petrocellis L., Anandamide: some like it hot, Trends Pharmacol. Sci. 22:346 (2001).PubMedCrossRefGoogle Scholar
  23. 23.
    V. Di Marzo, L. De Petrocellis, F. Fezza, A. Ligresti, and T. Bisogno, Anandamide Receptors, ProstaglLeukotr. Essent. Fatty Acids., 66:377–391 (2002).CrossRefGoogle Scholar
  24. 24.
    L. De Petrocellis, T. Bisogno, M. Maccarone, J. D. Davis, A. Finazzi-Agro, and V. Di Marzo, The activity of anandamide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabolism, J. Biol. Chem. 276:12856 (2001).PubMedCrossRefGoogle Scholar
  25. 25.
    V. Di Marzo, T. Bisogno, T. Sugiura, D. Melck, and L. De Petrocellis, The novel endogenous cannabinoid 2-arachidonoylglycerol is inactivated by neuronal-and basophil-like cells: connections with anandamide, Biochem. 7.331:15(1998).Google Scholar
  26. 26.
    C. J. Hillard, and A. Jarrahian, The movement of N-arachidonoylethanolamine (anandamide) across cellular membranes, Chem. Phys. Lipids 108:123 (2000).PubMedCrossRefGoogle Scholar
  27. 27.
    F. Fezza, T. Bisogno, A. Minassi, G. Appendino, R. Mechoulam, and V. Di Marzo, Inactivation mechanisms and a sensitive method for the quantification of the putative novel endocannabinoid, noladin ether, in rat brain tissue and cells, FEBS Letts., 513:294–298 (2002).CrossRefGoogle Scholar
  28. 28.
    C. J. Hillard, W. S. Edgemond, A. Jarrahian, and W. B. Campbell, Accumulation of N-arachidonoylethanolamine (anandamide) into cerebellar granule cells occurs via facilitated diffusion, J. Neurochem. 69:631 (1997).PubMedCrossRefGoogle Scholar
  29. 29.
    B. F. Cravatt, D. K. Giang, S. P. Mayfield, D. L. Boger, R. A. Lerner, and N. B. Gilula, Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides, Nature 384:83 (1996).PubMedCrossRefGoogle Scholar
  30. 30.
    N. Ueda, R. A. Puffenbarger, S. Yamamoto, and D. G. Deutsch, The fatty acid amide hydrolase (FAAH), Chem. Phys. Lipids 108:107 (2000).PubMedCrossRefGoogle Scholar
  31. 31.
    B. F. Cravatt, K. Demarest, M. P. Patricelli, M. H. Bracey, D. K. Giang, R. R. Martin, and A. H. Lichtman, Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase, Proc. Natl Acad. Sci. U.S.A. 98:9371 (2001).PubMedCrossRefGoogle Scholar
  32. 32.
    V. Di Marzo, L. De Petrocellis, and T. Bisogno, Emerging Therapeutic Targets from the Endocannabinoid System. 1. Molecular bases of endocannabinoid formation, action and inactivation, and development of selective inhibitors, Emerging Therapeutic Targets 5:241 (2001).CrossRefGoogle Scholar
  33. 33.
    A. C. Howlett, and S. Mukhopadhyay, Cellular signal transduction by anandamide and 2-arachidonoylglycerol, Chem. Phys. Lipids 108:53 (2000).PubMedCrossRefGoogle Scholar
  34. 34.
    V. Di Marzo, D. Melck, T. Bisogno, L. De Petrocellis, Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action, Trends Neurosci. 21:521 (1998).PubMedCrossRefGoogle Scholar
  35. 35.
    E. Schlicker, and M. Kathmann, Modulation of transmitter release via presynaptic cannabinoid receptors; Trends Pharmacol. Sci. 22:565 (2001).PubMedCrossRefGoogle Scholar
  36. 36.
    C. Levenes, H. Daniel, P. Soubrie, and F. Crepel, Cannabinoids decrease excitatory synaptic transmission and impair long-term depression in rat cerebellar Purkinje cells, J. Physiol. 510:867 (1998).PubMedCrossRefGoogle Scholar
  37. 37.
    B. Szabo, I. Wallmichrath, P. Mathonia, and C. Pfreundtner, Cannabinoids inhibit excitatory neurotransmission in the substantia nigra pars reticulata, Neuroscience 97:89 (2000).PubMedCrossRefGoogle Scholar
  38. 38.
    V. Morisset, and L. Urban, Cannabinoid-induced presynaptic inhibition of glutamatergic EPSCs in substantia gelatinosa neurons of the rat spinal cord, J. NeurophysioL 86:40 (2001).PubMedGoogle Scholar
  39. 39.
    D. Robbe, G. Alonso, F. Duchamp, J. Bockaert, and O. J. Manzoni, Localization and mechanisms of action of cannabinoid receptors at the glutamatergic synapses of the mouse nucleus accumbens, J. Neurosci. 21:109(2001).Google Scholar
  40. 40.
    C. W. Vaughan, M. Connor, E. E. Bagley, and M. J. Christie, Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro, Mol. Pharmacol. 57:288 (2000).PubMedGoogle Scholar
  41. 41.
    N. Auclair, S. Otani, P. Soubrie, and F. Crepel, Cannabinoids modulate synaptic strength and plasticity at glutamatergic synapses of rat prefrontal cortex pyramidal neurons, J. NeurophysioL 83:3287 (2000).PubMedGoogle Scholar
  42. 42.
    L. Ferraro, M. C. Tomasini, G. L. Gessa, B. W. Bebe, S. Tanganelli, and T. Antonelli, The cannabinoid receptor agonist WIN 55,212–2 regulates glutamate transmission in rat cerebral cortex: an in vivo and in vitro study, Cereh Cortex; 11:728(2001).Google Scholar
  43. 43.
    N. Hajos, C. Ledent, and T. F. Freund, Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus, Neuroscience 106:1(2001).Google Scholar
  44. 44.
    P. K. Chan, S. C. Chan, and W. H. Yung, Presynaptic inhibition of GABAergic inputs to rat substantia nigra pars reticulata neurones by a cannabinoid agonist, Neuroreport 9:671 (1998).PubMedCrossRefGoogle Scholar
  45. 45.
    K. Tsou, K. Mackie, M. C. Sanudo-Pena, and J. M. Walker, Cannabinoid CB1 receptors are localized primarily on cholecystokinin-containing GABAergic interneurons in the rat hippocampal formation, Neuroscience 93:969 (1999).PubMedCrossRefGoogle Scholar
  46. 46.
    I. Katona, B. Sperlagh, Z. Magloczky, E. Santha, A. Kofalvi, S. Czirjak, K. Mackie, E. S. Vizi, and T. F. Freund T. F., GABAergic interneurons are the targets of cannabinoid actions in the human hippocampus, Neuroscience 100:797 (2000).PubMedCrossRefGoogle Scholar
  47. 47.
    C. W. Vaughan, I. S. McGregor, and M. J. Christie M, Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro, Br. J. Pharmacol. 127:935 (1999).PubMedCrossRefGoogle Scholar
  48. 48.
    E. A. Jennings, C. W. Vaughan, and M. J. Christie M. J., Cannabinoid actions on rat superficial medullary dorsal horn neurons in vitro, J. Physiol. 534:805 (2001).PubMedCrossRefGoogle Scholar
  49. 49.
    J. Romero, R. de Miguel, J. A. Ramos, and J. J. Fernandez-Ruiz, The activation of cannabinoid receptors in striatonigral GABAergic neurons inhibited GABA uptake, Life Sci. 62:351 (1998).PubMedCrossRefGoogle Scholar
  50. 50.
    Y. P. Maneuf, J. E. Nash, A. R. Crossman, and J. M. Brotchie, Activation of the cannabinoid receptor by delta 9-tetrahydrocannabinol reduces gamma-aminobutyric acid uptake in the globus pallidus, Eur. J. Pharmacol 308:16 (1996).CrossRefGoogle Scholar
  51. 51.
    R. I. Wilson, and R. A. Nicoll, Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses, Nature 410:588 (2001).PubMedCrossRefGoogle Scholar
  52. 52.
    A. C. Kreitzer, and W. G. Regehr, Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells, Neuron 29:717 (2001).PubMedCrossRefGoogle Scholar
  53. 53.
    M. A. Diana, C. Levenes, K. Mackie, and A. Marty, Short-Term Retrograde Inhibition of GABAergic Synaptic Currents in Rat Purkinje Cells Is Mediated by Endogenous Cannabinoids, J. Neurosci. 22:200 (2002).PubMedGoogle Scholar
  54. 54.
    T. Maejima, K. Hashimoto, T. Yoshida, A. Aiba, and M. Kano, Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors, Neuron 31:463 (2001).PubMedCrossRefGoogle Scholar
  55. 55.
    R. I. Wilson, G. Kunos, and R. A. Nicoll, Presynaptic specificity of endocannabinoid signaling in the hippocampus, Neuron 31:453 (2001).PubMedCrossRefGoogle Scholar
  56. 56.
    N. Varma, G. C. Carlson, C. Ledent, and B. E. Alger, Metabotropic glutamate receptors drive the endocannabinoid system in hippocampus, J. Neurosci.21:RC188 (2001).PubMedGoogle Scholar
  57. 57.
    A. S. Rice, Cannabinoids and pain, Curr. Opin. Investig. Drugs 2:399 (2001).PubMedGoogle Scholar
  58. 58.
    R. G. Pertwee, Cannabinoid receptors and pain, Prog. Neurobiol 63:569 (2001).PubMedCrossRefGoogle Scholar
  59. 59.
    C. Ledent, O. Valverde, G. Cossu, F. Petitet, J. F. Aubert, F. Beslot, G. A. Bohme, A. Imperato, T. Pedrazz-ini, B. P. Roques, G. Vassart, W, Fratta, and M. Parmentier, Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice, Science 283:401 (1999).PubMedCrossRefGoogle Scholar
  60. 60.
    A. Zimmer, A. M. Zimmer, A. G. Hohmann, M. Herkenham, and T. I. Bonner, Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice, Proc. Natl. Acad. Sci. U.S.A. 96:5780 (1999).PubMedCrossRefGoogle Scholar
  61. 61.
    J. M. Walker, S. M. Huang, N. M. Strangman, K. Tsou, and M. C. Sanudo-Pena, Pain modulation by release of the endogenous cannabinoid anandamide, Proc. Natl. Acad. Sci. U.S.A. 96:12198 (1999).PubMedCrossRefGoogle Scholar
  62. 62.
    I. D. Meng, B. H. Manning, W. J. Martin, and H. L. Fields, An analgesia circuit activated by cannabinoids, Nature 395:381 (1998).PubMedCrossRefGoogle Scholar
  63. 63.
    J. D. Richardson, L. Aanonsen, and K. M. Hargreaves, Hypoactivity of the spinal cannabinoid system results in NMDA-dependent hyperalgesia, J. Neurosci. 18:451 (1998).PubMedGoogle Scholar
  64. 64.
    J. D. Richardson, S. Kilo,and K. M. Hargreaves, Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors, Pain 75:111 (1998).PubMedCrossRefGoogle Scholar
  65. 65.
    A. Calignano, G. La Rana, A. Giuffrida, and D. Piomelli, Control of pain initiation by endogenous cannabinoids, Nature 394:277 (1998).PubMedCrossRefGoogle Scholar
  66. 66.
    L. Hanus, A. Breuer, S. Tchilibon, S. Shiloah, D. Goldenberg, M. Horowitz, R. G. Pertwee, R. A. Ross, R. Mechoulam, and E. Fride, HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor, Proc. Natl. Acad. Sci. U.S.A. 96:14228 (1999).PubMedCrossRefGoogle Scholar
  67. 67.
    P. Beaulieu, T. Bisogno, S. Punwar, W. P. Farquhar-Smith, G. Ambrosino, V. Di Marzo, and A. S. Rice, Role of the endogenous cannabinoid system in the formalin test of persistent pain in the rat, Eur. J. Pharmacol. 396:85 (2000).CrossRefGoogle Scholar
  68. 68.
    W. P. Farquhar-Smith, and A. S. Rice, Administration of endocannabinoids prevents a referred hyperalgesia associated with inflammation of the urinary bladder, Anesthesiology 94:507 (2001).PubMedCrossRefGoogle Scholar
  69. 69.
    A. Calignano, G. La Rana, and D. Piomelli, Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide, Eur. J. Pharmacol. 419:191 (2001).PubMedCrossRefGoogle Scholar
  70. 70.
    D. J. Mason, J. Lowe, and S. P. Welch, Cannabinoid modulation of dynorphin A: correlation to cannabinoid-induced antinociception, Eur. J. Pharmacol. 378:237 (1999).PubMedCrossRefGoogle Scholar
  71. 71.
    S. P. Welch, and M. Eads, Synergistic interactions of endogenous opioids and cannabinoid systems, Brain Res. 848:183 (1999).PubMedCrossRefGoogle Scholar
  72. 72.
    S. P. Welch, Characterization of anandamide-induced tolerance: comparison to delta 9-THC-induced interactions with dynorphinergic systems, Drug Alcohol Depend. 45:39 (1997).PubMedCrossRefGoogle Scholar
  73. 73.
    V. Di Marzo, C. Breivogel, T. Bisogno, D. Melck, G. Patrick, Q. Tao, A. Szallasi, R. K. Razdan, and B. R. Martin, Neurobehavioral activity in mice of N-vanillyl-arachidonyl-amide, Eur. J. Pharmacol. 406:363 (2000).PubMedCrossRefGoogle Scholar
  74. 74.
    J. W. Brooks, G. Pryce, T. Bisogno, S. I. Jaggar, D. J. R. Hankey, P. Brown, D. Bridges, C. Ledent, M. Bifulco, A. S. C. Rice, V. Di Marzo, and D. Baker, Arvanil-induced inhibition of spasticity and persistent pain: evidence for therapeutic non-VRl, non-CBi, non-CB2 sites of action, Eur. J. Pharmacol., 439:83–92 (2002).PubMedCrossRefGoogle Scholar
  75. 75.
    M. Tognetto, S. Amadesi, S. Harrison, C. Creminon, M. Trevisani, M. Carreras, M. Matera, P. Geppetti, and A. Bianchi, Anandamide excites central terminals of dorsal root ganglion neurons via vanilloid receptor-1 activation, J. Neurosci. 21:1104 (2001).PubMedGoogle Scholar
  76. 76.
    S. D. Gauldie, D. S. McQueen, R. Pertwee, and I. P. Chessell, Anandamide activates peripheral nociceptors in normal and arthritic rat knee joints, Br. J. Pharmacol. 132:617 (2001).PubMedCrossRefGoogle Scholar
  77. 77.
    J. Harris, L. J. Drew, V. Chapman, Spinal anandamide inhibits nociceptive transmission via cannabinoid receptor activation in vivo, Neuroreport 11:2817 (2000).PubMedCrossRefGoogle Scholar
  78. 78.
    V. Morisset, J. Ahluwalia, I. Nagy, and L. Urban, Possible mechanisms of cannabinoid-induced antinociception in the spinal cord, Eur. J. Pharmacol. 429:93 (2001).PubMedCrossRefGoogle Scholar
  79. 79.
    J. Ahluwalia, L. Urban, M. Capogna, S. Bevan, and I. Nagy I., Cannabinoid 1 receptors are expressed in nociceptive primary sensory neurons, Neuroscience 100, 685 (2000).PubMedCrossRefGoogle Scholar
  80. 80.
    B. F. Cravatt, O. Prospero-Garcia, G. Siuzdak, N. B. Gilula, S. J. Henriksen, D. L. Boger, R. A. Lerner, Chemical characterization of a family of brain lipids that induce sleep, Science 268:1506 (1995).PubMedCrossRefGoogle Scholar
  81. 81.
    I. Fedorova, A. Hashimoto, R. A. Fecik, M. P. Hedrick, L. O. Hanus, D. L. Boger, K. C. Rice, and A. S. Basile, Behavioral evidence for the interaction of oleamide with multiple neurotransmitter systems, J. Pharmacol. Exp. Ther. 299:332 (2001).PubMedGoogle Scholar
  82. 82.
    D. L. Boger, S. J. Henriksen, and B. F. Cravatt, Oleamide: an endogenous sleep-inducing lipid and prototypical member of a new class of biological signaling molecule,. Curr. Pharm. Des. 4:303 (1998).PubMedGoogle Scholar
  83. 83.
    W. B. Mendelson, and A. S. Basile, The hypnotic actions of the ratty acid amide, oleamide, Neuropsycho-pharmacology 25:S36 (2001).CrossRefGoogle Scholar
  84. 84.
    J. F. Cheer, A. K. Cadogan, C. A. Marsden, K. C. Fone, and D. A. Kendall, Modification of 5-HT2 receptor mediated behaviour in the rat by oleamide and the role of cannabinoid receptors, Neuropharmacology 38:533 (1999).PubMedCrossRefGoogle Scholar
  85. 85.
    W. B. Mendelson, and A. S. Basile, The hypnotic actions of oleamide are blocked by a cannabinoid receptor antagonist, euroreport 10:3237 (1999).CrossRefGoogle Scholar
  86. 86.
    R. Mechoulam, E. Fride, L. Hanus, T. Sheskin, T. Bisogno, V. Di Marzo, M. Bayewitch, and Z. Vogel, Anandamide may mediate sleep induction, Nature 389:25 (1997).PubMedCrossRefGoogle Scholar
  87. 87.
    V. Santucci, J. J. Storme, P. Soubrie, and G. Le Fur, Arousal-enhancing properties of the CB1 cannabinoid receptor antagonist SR 141716A in rats as assessed by electroencephalographic spectral and sleep-waking cycle analysis, Life Sci. 58:PL103 (1996).PubMedCrossRefGoogle Scholar
  88. 88.
    M. Martinez-Vargas, E. Murillo-Rodriguez, R. Gonzalez-Rivera, A. Landa, J. Velazquez-Moctezuma, O. Prospero-Garcia, and L. Navarro, Cannabinoid receptor 1 increases with sleep rebound, Soc. Neurosci. Abstr. 524.22 (2001).Google Scholar
  89. 89.
    E. Murillo-Rodriguez, A. Giuffrida, F. Desarnaud, O. Prospero-Garcia, and D. Piomelli, Diurnal variations of endogenous cannabinoid compounds in csf and brain regions of the rat, Soc. Neurosci. Abstr. 805.2 (2001)Google Scholar
  90. 90.
    G. Lees, M. D. Edwards, A. A. Hassoni, C. R. Ganellin, and D. Galanakis, Modulation of GABA(A) receptors and inhibitory synaptic currents by the endogenous CNS sleep regulator cis-9,10-octadecenoamide (cOA), Br. J. Pharmacol. 124:873 (1998).PubMedCrossRefGoogle Scholar
  91. 91.
    A. D. Laposky, G. E. Homanics, A. Basile, and W. B. Mendelson, Deletion of the GABA(A) receptor beta 3 subunit eliminates the hypnotic actions of oleamide in mice, Neuroreport 12:4143 (2001).PubMedCrossRefGoogle Scholar
  92. 92.
    M. D. Aceto, S. M. Scates, R. K. Razdan, B. R. Martin, Anandamide, an endogenous cannabinoid, has a very low physical dependence potential, J. Pharmacol. Exp. Ther. 287:598 (1998).PubMedGoogle Scholar
  93. 93.
    T. W. Klein, B. Lane, C. A. Newton, and H. Friedman, The cannabinoid system and cytokine network, Proc. Soc. Exp. Biol. Med. 225:1 (2000).PubMedCrossRefGoogle Scholar
  94. 94.
    G. Kunos, Z. Jarai, S. Batkai, S. K. Goparaju, E. J. Ishac, J. Liu, L. Wang, and J. A. Wagner, Endocannabinoids as cardiovascular modulators, Chem. Phys. Lipids 108:159 (2000).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Luciano De Petrocellis
  • Tiziana Bisogno
  • Vincenzo Di Marzo
    • 1
  1. 1.Institutes di Biomolecular Chemistry and CyberneticsEndocannabinoid Research GroupPozzuoli (Napoli)Italy

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