Endogenous cannabinoids - A local message in and between the nervous and immune system

Signal Transduction

Volumn 5, Issue 1-2, 2005, Pages 19-27

  Ullrich, Oliver ^a   Schneider Stock, Regine ^a  

^a OTTO VON GUERICKE UNIVERSITY   (Germany)

Author keywords

Apoptosis; G proteins; Immune cells; Neurotransmission; Synapse

Indexed keywords

CANNABINOID RECEPTOR; ENDOCANNABINOID; LIGAND;

CELL COMMUNICATION; CELL DEATH; CELL PROLIFERATION; CENTRAL NERVOUS SYSTEM; DEGRADATION KINETICS; ENZYME SYNTHESIS; HUMAN; IMMUNE SYSTEM; INTRACELLULAR TRANSPORT; NERVOUS SYSTEM; NEUROTRANSMISSION; PRIORITY JOURNAL; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION;

EID: 18344367846     PISSN: 16154053     EISSN: None     Source Type: Journal    
DOI: 10.1002/sita.200400043     Document Type: Review

References (117)

1. Rouyer, M. (1810) Sur les medicaments usuels des Egyptiens. Bull. Pharmacie 2: 25.
2. Christison, R. (1848) On the Natural History, Action, and Uses of Indian Hemp. In A Dispensatory, or Commentary on the Pharmacopoeias of Great Britain (and the United States). Lea and Blanchard, Philadelphia (USA) 971-974.
3. Mechoulam, R. (1986) The pharmacohistory of Cannabis sativa. In Cannabinoids as Therapeutic Agents. Ed. Mechoulam, R., CRC Press, Boca Raton, FL (USA) 1-19.
4. Gaoni, Y., Mechoulam, R. (1964) Isolation, structure elucidation and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86: 1646-1647.
5. Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C., Bonner, T.I. (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346: 561-564.
6. Munro, S., Thomas, K.L., Abu-Shaar, M. (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365: 61-65.
7. Devane, W.A., Hanus, L., Breuer, A., Pertwee, R.G., Stevenson, L.A., 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 256: 1946-1949.
8. Mechoulam, R., Ben-Shabat, S., Hanus, L., Ligumsky, M., Kaminski, N.E., Schatz, A.R., Gopher, A., Almog, S., Martin, B.R., Compton, D.R., Pertwee, R.G., Griffin, G., Bayewitch, M., Barg, J., Vogel, Z. (1995) Identification of an endogenous 2 monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50: 83-90.
9. Devane, W. A., Dysarz, F. A., Johnson, M. R., Melvin, L. S., Howlett, A. C. (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34: 605-613.
10. Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C., Bronner, T.I.(1988) Structure of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34: 605-613.
11. 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.
12. Giuffrida, A., Parsons, L.H., Kerr, TM., Rodriguez de Fonseca, F., Navarro, M., Piomelli, D. (1999) Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nature Neurosci. 2: 358-363.
13. Walker, J. M., Huang, S. M., Strangman, N. M., Tsou, K., Sañudo-Peña, M. C. (1999) Pain modulation by release of the endogenous cannabinoid anandamide. Proc. Natl Acad. Sci. USA 96: 12198-12203.
14. Sugiura, T., Kondo, S., Sukagawa, A., Nakane, S., Shinoda, A., Itoh, K., Yamashita, A., Waku, K. (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215: 89-97.
15. Piomelli, D., Greengard, P. (1990) Lipoxygenase metabolites of arachidonic acid in neuronal transmembrane signalling. Trends Pharmacol. Sci. 11: 367-373.
16. Piomelli, D. (2003) The molecular logic of endocannabinoid signalling. Nat. Rev. Neurosci. 4: 873-884.
17. Hanus, L., Abu-Lafi, S., Fride, E., Breuer, A., Vogel, Z., Shalev, D.E., Kustanovich, I., Mechoulam, R. (2001) 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB, receptor. Proc. Natl Acad. Sci. USA 98: 3662-3665.
18. Porter, A. C. et al. (2002) Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J. Pharmacol. Exp. Ther. 301: 1020-1024.
19. Huang, S. M., Bisogno, T., Trevisani, M., Al-Hayani, A., De Petrocellis, L., Fezza, F., Tognetto, M., Petros, T.J., Krey, J.F., Chu, C.J., Miller, J.D., Davies, S.N., Geppetti, P., Walker, J.M., Di Marzo, V. (2002) An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc. Natl Acad. Sci. USA 99: 8400-8405.
20. Chapman, K. D. (2000) Emerging physiological roles for N-acylphosphatidylethanolamine metabolism in plants: signal transduction and membrane protection. Chem. Phys. Lipids 108: 221-229.
21. Sugiura, T., Kondo, S., Sukagawa, A., Tonegawa, T., Nakane, S., Yamashita, A., Ishima, Y., Waku, K. (1996) Transacylase-mediated and phosphodiesterase-mediated synthesis of N-arachidonoylethanolamine, an endogenous cannabinoid-receptor ligand, in rat brain microsomes. Comparison with synthesis from free arachidonic acid and ethanolamine. Eur. J. Biochem. 240: 53-62.
22. Cadas, H., di Tomaso, E., Piomelli, D. (1997) Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J. Neurosci. 17: 1226-1242.
23. Senogles, S.E. (2000) The D2s dopamine receptor stimulates phospholipase D activity: a novel signalling pathway for dopamine. Mol. Pharmacol. 58: 455-462.
24. 2+ currents and excitability via a novel PLCβ1-IP3-calcineurin-signaling cascade. J. Neurosci. 20: 8987-8995.
25. Varma, N., Carlson, G. C., Ledent, C., Alger, B. E. (2001) Metabotropic glutamate receptors drive the endocannabinoid system in hippocampus. J. Neurosci. 21: RC188.
26. Kim, J., Isokawa, M., Ledent, C., Alger, B. E. (2002) Activation of muscarinic acetylcholine receptors enhances the release of endogenous cannabinoids in the hippocampus J. Neurosci. 22: 10182-10191.
27. Stella, N., Schweitzer, P., Piomelli, D. (1997) A second endogenous cannabinoid that modulates long-term potentiation. Nature 399: 773-778.
28. Stella, N., Piomelli, D. (2001) Receptor-dependent formation of endogenous cannabinoids in cortical neurons. Eur. J. Pharmacol. 425: 189-196.
29. DiMarzo, V., Bisogno, T., de Petrocellis, L., Melck, D., Orlando, P., Wagner, J.A., Kunos, G. (1999) Biosynthesis and inactivation of the endocannabinoid 2-arachidonoyl-glycerol in circulating and tumoral macrophages. Eur. J. Biochem. 264: 258-267.
30. Walter, L., Stella, N. (2004) Cannabinoids and neuroinflammation. Br. J. Pharmacol. 141: 775-785.
31. Walter, L., Franklin, A., Witting, A., Wade, C., Xie, Y., Kunos, G., Mackie, K., Stella, N. (2003) Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J. Neurosci. 23: 1398-1405.
32. Song, Z. H., Bonner, T. I. (1996) A lysine residue of the cannabinoid receptor is critical for receptor recognition by several agonists but not WIN55212-2. Mol. Pharmacol. 49: 891-896.
33. Wilson, R. I., Nicoll, R. A. (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410: 588-592.
34. Kreitzer, A. C., Regehr, W. G. (2001) Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 29: 717-727.
35. Ohno-Shosaku, T., Maejima, T., Kano, M. (2001) Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29: 729-738.
36. Gerdeman, G. L., Ronesi, J., Lovinger, D. M. (2002) Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nature Neurosci. 5: 446-451.
37. Robbe, D., Kopf, M., Remaury, A., Bockaert, J., Manzoni, O. J. (2002) Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc. Natl Acad. Sci. USA 99: 8384-8388.
38. Chevaleyre, V., Castillo, P. E. (2003) Heterosynaptic LTD of hippocampal GABAergic synapses. A novel role of endocannabinoids in regulating excitability. Neuron 38: 461-472.
39. Bojensen, I. N., Hansen, H. S. (2003) Binding of anandamide to bovine serum albumin. J. Lipid Res. 44: 1790-1794.
40. Beltramo, M., Stella, N., Calignano, A., Lin, S.Y., Makriyannis, A., Piomelli, D. (1997) Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277: 1094-1097.
41. Hillard, C. J., Edgemond, W. S., Jarrahian, A., Campbell, W. B. (1997) Accumulation of N-arachidonoylethanolamine (anandamide) into cerebellar granule cells occurs via facilitated diffusion. J. Neurochem. 69: 631-638.
42. Glaser, S.T., Abumrad, N.A., Fatade, F., Kaczocha, M., Studholme, K.M., Deutsch, D.G. (2003) Evidence against the presence of an anandamide transporter. Proc. Natl. Acad. Sci. U.S.A. 100: 4269-4274.
43. Schmid, P. C., Zuzarte-Augustin, M. L., Schmid, H. H. (1985) Properties of rat liver N-acylethanolamine amidohydrolase. J. Biol. Chem. 260: 14145-14149.
44. Hillard, C. J., Wilkison, D. M., Edgemond, W. S., Campbell, W. B. (1995) Characterization of the kinetics and distribution of N-arachidonylethanolamine (anandamide) hydrolysis by rat brain. Biochim. Biophys. Acta 1257: 249-256.
45. Ueda, N., Kurahashi, Y., Yamamoto, S., Tokunaga, T. (1995) Partial purification and characterization of the porcine brain enzyme hydrolyzing and synthesizing anandamide. J. Biol. Chem. 270: 23823-23827.
46. Cravatt, B. F., Giang, D.K., Mayfield, S.P., Boger, D.L., Lerner, R.A., Gilula, N.B. (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384: 83-87.
47. Tsou, K., Nogueron, M.I., Muthian, S., Sanudo-Pena, M.C., Hillard, C.J., Deutsch, D.G., Walker, J.M. (1998) Fatty acid amide hydrolase is located preferentially in large neurons in the rat central nervous system as revealed by immunohistochemistry. Neurosci. Lett. 254: 137-140.
48. 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: 481-496.
49. Romero, J., Hillard, C.J., Calero, M., Rabano, R. (2002) Fatty acid amide hydrolase localization in the human central nervous system: an immunohistochemical study. Brain Res. Mol. Brain Res. 100: 85-93.
50. Maccarrone, M., diRienzo, M., Finazzi-Agro, A., Rossi, A. (2003) Leptin activates the anandamide hydrolase promoter in human T lymphocytes through STAT3. J. Biol. Chem. 278: 13318-13324.
51. Matias, I., Pochard, P., Orlando, P., Salzet, M., Pestel, J., Di Marzo, V. (2002) Presence and regulation of the endocannabinoid system in human dendritic cells. Eur. J. Biochem. 269: 3771-3778.
52. Dinh, T. P. et al. (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc. Natl Acad. Sci. USA 99: 10819-10824.
53. Edgemond, W.S., Hillard, J.H., Falck, J.R., Kearn, C.S., Campbell, W.B. (1998) Human platelets and polymorphonuclear leukocytes synthesize oxygenated derivatives of arachodonoylethanolamine (anadamide): their affinities for cannabinoid receptors and pathways of inactivation. Mol. Pharmacol. 54: 180-188.
54. Chang, Y.H., Lee, S.T., Lin, W.W. (2001) Effects of cannabinoids on LPS-stimulated inflammatory mediator release from macrophages: involvement of eicosanoids. J. Cell Biochem. 81: 715-723.
55. Herkennam, M., Lynn, A.B., Little, M.D., Johnson, M.R., Melvin, L.S., de Costa, B.R., Rice, K.C. (1990) Cannabinoid receptor localization in brain. Proc. Natl Acad. Sci. USA 87: 1932-1936.
56. Howlett, A.C. (1984) Inhibition of neuroblastoma adenylate cyclase by cannabinoid and nantradol compounds. Life Sci. 35: 1803-1813.
57. Mackie, K., Hille, B. (1992) Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc. Natl Acad. Sci. USA 89: 3825-3829.
58. Caulfield, M. P., Brown, D. A. (1992) Cannabinoid receptor agonists inhibit Ca current in NG108-15 neuroblastoma cells via a pertussis toxin-sensitive mechanism. Br. J. Pharmacol. 106: 231-232.
59. Twitchell, W., Brown, S., Mackie, K. (1997) Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons. J. Neurophysiol. 78: 43-50.
60. A synaptic transmission in the hippocampus. J. Neurosci. 20: 2470-2479.
61. Gerdeman, G., Lovinger, D. M. (2001) CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum. J. Neurophysiol. 85: 468-471.
62. Huang, C. C., Lo, S. W., Hsu, K. S. (2001) Presynaptic mechanisms underlying cannabinoid inhibition of excitatory synaptic transmission in rat striatal neurons. J. Physiol. 532: 731-748.
63. Mu, J., Zhuang, S. Y., Kirby, M. T., Hampson, R. E., Deadwyler, S. A. (1999) Cannabinoid receptors differentially modulate potassium A and D currents in hippocampal neurons in culture. J. Pharmacol. Exp. Ther. 291: 893-902.
64. Derkinderen, P., Toutant, M., Burgaya, F., Le Bert, M., Siciliano, J.C., de Franciscis, V., Gelman, M., Girault, J.A. (1996) Regulation of a neuronal form of focal adhesion kinase by anandamide. Science 273: 1719-1722.
65. Derkinderen, P., Valjent, E., Toutant, M., Corvol, J.C., Enslen, H., Ledent, C., Trzaskos, J., Caboche, J., Girault, J.A. (2003) Regulation of extracellular signal-regulated kinase by cannabinoids in hippocampus. J. Neurosci. 23: 2371-2382.
66. Wartmann, M., Campbell, D., Subramanian, A., Burstein, S.H., Davis, R.J. (1995) The MAP kinase signal transduction pathway is activated by the endogenous cannabinoid anandamide. FEBS Lett. 359: 133-136.
67. Bouaboula, M., Bourrie, B., Rinaldi-Carmona, M., Shire, D., Le Fur, G., Casellas, P. (1995) Stimulation of cannabinoid receptor CB1 induces krox-24 expression in human astrocytoma cells. J. Biol. Chem. 270: 13973-13980.
68. Bouaboula, M., Poinot Chazel, C., Bourrie, B., Canat, X., Calandra, B., Rinaldi Carmona, M., Le Fur, G., Casellas, P. (1995) Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. Biochem. J. 312: 637-641.
69. Bouaboula, M., Poinot Chazel, C., Marchand, J., Canat, X., Bourrie, B., Rinaldi Carmona, M., Calandra, B., Le Fur, G., Casellas, P. (1996) Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression. Eur. J. Biochem. 237: 704-711.
70. Liu, J., Gao, B., Mirshahi, F., Sanyal, A.J., Khanolkar, A.D., Makriyanis, A., Kunos, G. (2000) Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem. J. 346: 835-840.
71. Rueda, D., Galve-Roperh, I., Haro, A., Guzman, M. (2000) The CB1 cannabinoid receptor is coupled to the action of c-Jun N-terminal kinase. Mol. Pharmacol. 58: 814-820.
72. Gomez del Pulgar, T., Velasco, G., Guzman, M. (2000) The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt. Biochem. J. 347: 369-373.
73. Pertwee, R.G. (2000) Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development. Exp. Opin. Invest. Drugs 9: 1-19.
74. Porter, A.C., Felder, C.C. (2001) The endocannabinoid nervous system: unique opportunities for therapeutic intervention. Pharmacol. Ther. 90: 45-60.
75. Galiegue, S., Mary, S., Marchand, J., Dussossoy, D., Carriere, D., Carayon, P., Bouaboula, M., Shire, D., Le Fur, G., Casellas, P. (1995) Expression of central and peripheral cannabinoid receptors in human immune tissue and leukocyte subpopulations. Eur. J. Biochem. 232: 54-61.
76. Kaminski, N.E. (1998) Regulation of the cAMP cascade, gene expression and immune function by cannabinoid receptors. J. Neuroimmunol. 83: 124-132.
77. Sanchez, C., deCeballos, M.L., DelPulgar, T.G., Rueda, D., Corbacho, C., Velasco, G., Galve-Roperh, I., Hoffman, J.W., Ramon y Cajal, S., Guzman, M. (2001) Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res. 61: 5784-5789.
78. 9-tetrahydrocannabinol-induced stimulation of glucose metabolism in primary astrocytes. Mol. Pharmacol. 54: 834-843.
79. Galve-Roperh, I., Sanchez, C., Cortes, L., del Pulgar, T.G., Izquierdo, M., Guzman, M. (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal regulated kinase activation. Nat. Med. 6: 313-319.
80. Guzman, M., Sanchez, C., Galve-Roperh, I. (2001) Control of the cell survival/death decision by cannabinoids. J. Mol. Med. 78: 613-625.
81. Sanchez, C., Galve-Roperh, I., Canova, C., Brachet, P., Guzman, M. (1998) Δ9-tetrahydrocannabinoid induces apoptosis in C6 glioma cells. FEBS Lett. 436: 6-10.
82. Jacobsson, S.O., Rongard, E., Stridh, M., Tiger, G., Fowler, C.J. (2000) Serum-dependent effects of tamoxifen and cannabinoids upon C6 glioma cell viability. Biochem. Pharmacol. 60: 1807-1813.
83. Sarker, K.P., Obara, S., Nakata, M., Kitajima, I., Maruyama, I. (2000) Anandamide induces apoptosis of PC-12 cells: involvement of superoxide and caspase-3. FEBS Lett. 472: 34-44.
84. Maccarrone, M., Lorenzon, T., Bari, M. et al. (2000) Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors. J. Biol. Chem. 275: 31938-31945.
85. Zygmunt, P.M., Petersson, J., Andersson, D.A., Chuang, H., Sorgard, M. Di Marzo, V., Julius, D., Högestätt, E.D. (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400: 452-457.
86. Szolcsanyi, J. (2000) Anandamide and the question of its functional role for activation of capsaicin receptors. Trends Pharmacol. Sci. 21: 203-204.
87. Piomelli, D. (2001) The ligand that came from within. Trends Pharamcol. Sci. 22: 17-19.
88. Klegeris, A., Bissonnette, C.J., McGeer, P.L. (2003) Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. Br. J. Pharamacol. 139: 775-786.
89. Berdyshev, E.V., Boichot, E., Germain, N., Allain, N., Anger, J.P., Lagente, V. (1997) Influence of fatty acid ethanolamides and delta-9-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells. Eur. J. Pharmacol. 330: 231-240.
90. Gallily, R., Breuer, A., Mechoulam, R. (2000) 2-Arachidonylglycerol, an endogenous cannabinoid, inhibits tumor necrosis factor-alpha production in murine macrophages, and in mice. Eur. J. Pharmacol. 406: 5-7.
91. Stefano, G.B., Liu, Y., Goligorsky, M.S. (1996) Cannabinoid receptors are coupled to nitric oxide release in invertebrate immunocytes, microglia, and human monocytes. J. Biol. Chem. 271: 19238-19242.
92. Franklin, A., Parmentier-Batteur, S., Walter, L., Greenberg, D.A., Stella, N. (2003) Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. J. Neurosci. 23: 7767-7775.
93. 1 receptors mediate thevasodilated state in advanced liver cirrhosis. Nature Med. 7: 827-832.
94. Llano, I., Leresche, N., Marty, A. (1991) Calcium entry increases the sensitivity of cerebellar Purkinje cells to applied GABA and decreases inhibitory synaptic currents. Neuron 6: 565-574.
95. Kreitzer, A. C., Regehr, W. G. (2001) Cerebellar depolarization-induced suppression of inhibition is mediated by endogenous cannabinoids. J. Neurosci. 21: RC174.
96. Trettel, J., Levine, E. S. (2003) Endocannabinoids mediate rapid retrograde signaling at interneuron right-arrow pyramidal neuron synapses of the neocortex. J. Neurophysiol. 89: 2334-2338.
97. Navarro, M., Hernandez, E., Munoz, R.M., del Arco, I., Villanua, M.A., Carrera, M.R., Rodriguez de Fonseca, F. (1997) Acute administration of the CB1 cannabinoid receptor antagonist SR 141716A induces anxiety-like responses in the rat. Neuroreport 8: 491-496.
98. Martin, M., Ledent, C., Parmentier, M., Maldonado, R., Valverde, O. (2002) Involvement of CB1 cannabinoid receptors in emotional behaviour. Psychopharmacology (Berl.) 159: 379-387.
99. 9-tetrahydrocannabinol treatment induces sensitization to the psychomotor effects of amphetamine in rats. Eur. J. Pharmacol. 365: 133-142.
100. Sieradzan, K. A., Fox, S.H., Hill, M., Dick, J.P., Crossman, A.R., Brotchie, J.M. (2001) Cannabinoids reduce levodopa-induced dyskinesia in Parkinson's disease: a pilot study. Neurology 57: 2108-2111.
101. 9-Tetrahydro-cannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6-week randomized trial. J. Clin. Psychiatry 64: 459-465.
102. Iversen, L., Chapman, V. (2002) Cannabinoids: a real prospect for pain relief. Curr. Opin. Pharmacol. 2: 50-55.
103. Lichtman, A.H., Cook, S.A., Martin, B.R. (1996) Investigation of brain sites mediating cannabinoid-induced antinociception in rats: evidence supporting periaquaeductal gray involvement. J. Pharmacol. Exp. Then 276: 585-593.
104. Meng, I.D., Manning, B.H., Martin, W.J., Field, H.L. (1998) An analgesia circuit activated by cannabinoids. Nature 395: 381-383.
105. Jennings, E.A., Vaughan, C.W., Christie, M.J. (2001) Cannabinoid actions on rat superficial medullary dorsal horn neurons in vitro. J. Physiol. 534: 805-812.
106. Alger, B. E. (2002) Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog. Neurobiol. 68: 247-286.
107. Ohno-Shosaku, T., Tsubokawa, H., Mizushima, I., Yoneda, N., Zimmer, A., Kano, M. (2002) Presynaptic cannabinoid sensitivity is a major determinant of depolarization-induced retrograde suppression at hippocampal synapses. J. Neurosci. 22: 3864-3872.
108. Schlicker, E., Kathmann, M. (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharamcol. Sci. 22: 565-572.
109. Gifford, A.N., Ashby, C.R. Jr. (1996) Electrically evoked acetlycholine release from hippocampal slices is inhibited by the cannabinoid receptor agonist, WIN 55212-2, and is potentiated by the cannabinoid antagonist, SR 141716A. J. Pharmacol. Exp. Ther. 277: 1431-1436.
110. Cessa, G.L., Casu, M.A., Carta, G., Mascia, M.S. (1998) Cannabinoids decrease acetylcholine release in the medial-prefrontal cortex and hippocampus, reversal by SR 141716A. Eur. J. Pharmacol. 355: 119-124.
111. Panikashvili, D., Simeonidou, C., Ben-Shabat, S., Hanus, L., Breuer, A., Mechoulam, R., Shohami, E. (2001) An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413: 527-531.
112. Hansen, H.H., Schmid, P.C., Bittigau, P., Lastres-Becker, l., Berrendero, F., Manzanares, J., Ikonomidou, C., Schmid, H.H.O., Fernandez-Ruiz, J.J., Hansen, H.S. (2001) Anandamide, but not 2-arachidonoylglycerol, accumulates during in vivo neurodegeneration. J. Neurochem. 78: 1415-1427.
113. Marsicano, G., Goodenough, S., Monory, K., Hermann, H., Eder, M., Cannich, A., Azad, S.C., Cascio, M.G., Gutiérrez, S.O., van der Stelt, M., López-Rodríguez, M.L., Casanova, E., Schütz, G., Zieglgänsberger, W., Di Marzo, V., Behl, C., Lutz, B. (2003) CB1 Cannabinoid Receptors and On-Demand Defense Against Excitotoxicity. Science 302: 84-88.
114. Mechoulam, R., Lichtman, A.H. (2003) Stout Guards of the Central Nervous System. Science 302: 65-67.
115. Carrier, E.J., Kearn, C.S., Barkmeier, A.J., Breese, N.M., Yang, W., Nithipatikom, K., Pfister, S.L., Campbell, W.B., Hillard, C.J. (2004) Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism. Mol. Pharmacol. 65: 999-1007.
116. Facchinetti, F., Del Giudice, E., Furegato, S., Passarotto, M., Leon, A. (2003) Cannabinoids ablate release of TNFα in rat microglial cells stimulated withlypopolysaccharide. Glia 41: 161-168.
117. Waksman, Y., Olson, J.M., Carlisle, S.J., Cabral, G.A. (1999) The central cannabinoid receptor (CB1) mediates inhibition of nitric oxide production by rat microglial cells. J. Pharmacol. Exp. Ther. 288: 1357-1366.