Cannabinoid-based drugs as anti-inflammatory therapeutics

Nature Reviews Immunology

Volumn 5, Issue 5, 2005, Pages 400-411

  Klein, Thomas W ^a  

^a UNIVERSITY OF SOUTH FLORIDA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 ARACHIDONOYLGLYCEROL; 2 METHYL 3 (1 NAPHTHOYL) 1 PROPYLINDOLE; 2,3 DIHYDRO 5 METHYL 3 (MORPHOLINOMETHYL) 6 (1 NAPHTHOYL)PYRROLO[1,2,3 DE][1,4]BENZOXAZINE; 3 (2 IODO 5 NITROBENZOYL) 1 (1 METHYL 2 PIPERIDINYLMETHYL)INDOLE; 4 (1,1 DIMETHYLHEPTYL) 1',2',3',4',5',6' HEXAHYDRO 2,3' DIHYDROXY 6' (3 HYDROXYPROPYL)BIPHENYL; 5 (4 CHLORO 3 METHYLPHENYL) 1 (4 METHYLBENZYL) N (1,3,3 TRIMETHYLBICYCLO[2.2.1]HEPTAN 2 YL) 3 PYRAZOLECARBOXAMIDE; ACCOMPLIA; AJULEMIC ACID; ANANDAMIDE; ANTIINFLAMMATORY AGENT; CANNABIDIOL; CANNABINOID; CANNABINOID 1 RECEPTOR; CANNABINOID 2 RECEPTOR; CANNABINOID RECEPTOR ANTAGONIST; CANNABIS; DEXANABINOL; DRONABINOL; ENDOCANNABINOID; INDOLE DERIVATIVE; NONSTEROID ANTIINFLAMMATORY AGENT; RIMONABANT; UNCLASSIFIED DRUG;

ALLERGIC ENCEPHALOMYELITIS; ANTIINFLAMMATORY ACTIVITY; ARTHRITIS; CANCER; CANNABIS ADDICTION; CARDIOVASCULAR DISEASE; CELL MIGRATION; CHRONIC INFLAMMATION; CLINICAL TRIAL; CYTOKINE PRODUCTION; DRUG MECHANISM; EATING DISORDER; ENTERITIS; HEAD INJURY; HELPER CELL; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; INNATE IMMUNITY; MULTIPLE SCLEROSIS; NONHUMAN; OBESITY; PRIORITY JOURNAL; RABIES; REVIEW; SIDE EFFECT; SMOKING CESSATION; SPASTICITY; TREMOR;

ANIMALS; ANTI-INFLAMMATORY AGENTS; CANNABINOIDS; CELL MOVEMENT; CYTOKINES; HUMANS; IMMUNITY, NATURAL; INFLAMMATION; RECEPTORS, CANNABINOID; T-LYMPHOCYTES, HELPER-INDUCER;

EID: 18844400058     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri1602     Document Type: Review

References (124)

1. Tomida, I., Pertwee, R. G. & Azuara-Blanco, A. Cannabinoids and glaucoma. Br. J. Ophthalmol. 88, 708-713 (2004).
2. Guzman, M. Cannabinoids: potential anticancer agents. Nature Rev. Cancer 3, 745-755 (2003).
3. Kunos, G. & Pacher, P. Cannabinoids cool the intestine Nature Med. 10, 678-679 (2004).
4. Mendizabal, V. E. & Adler-Graschinsky, E. Cannabinoid system as a potential target for drug development in the treatment of cardiovascular disease. Curr. Vasc. Pharmacol. 1, 301-313 (2003).
5. Mechoulam, R., Panikashvili, D. & Shohami, E. Cannabinoids and brain injury: therapeutic implications. Trends Mol. Med. 8, 58-61 (2002).
6. Baker, D. & Pryce, G. The therapeutic potential of cannabis in multiple sclerosis. Expert Opin. Investig. Drugs 12, 561-567 (2003).
7. Baker, D., Pryce, G., Giovannoni, G. & Thompson, A. J. The therapeutic potential of cannabis. Lancet Neurol. 2, 291-298 (2003).
8. Di Marzo, V., Bifulco, M. & De Petrocellis, L. The endocannabinoid system and its therapeutic exploitation. Nature Rev. Drug Discov. 3, 771-784 (2004).
9. Black, S. C. Cannabinoid receptor antagonists and obesity. Curr. Opin. Investig. Drugs 5, 389-394 (2004).
10. Gaoni, Y. & Mechoulam, R. Isolation, structure, and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86, 1646-1647 (1964). This is a seminal paper that describes the isolation and synthesis of THC.
11. Howlett, A. C. et al. International Union of Pharmacology. XXVII. Classification of Cannabinoid receptors. Pharmacol. Rev. 54, 161-202 (2002). For those wanting more on the chemistry and biology of the Cannabinoid system, this is a recent and authoritative review.
12. Rhee, M. H. et al. Cannabinol derivatives: binding to Cannabinoid receptors and inhibition of adenylylcyclase. J. Med. Chem. 40, 3228-3233 (1997).
13. Zurier, R. B. et al. Dimethylheptyl-THC-11 oic acid. A nonpsychoactive antiinflammatory agent with a Cannabinoid template structure. Arthritis Rheum. 41, 163-170 (1996).
14. Burstein, S. H. The Cannabinoid acids: nonpsychoactive derivatives with therapeutic potential. Pharmacol. Ther. 82, 87-96 (1999).
15. Liu, J., Li, H., Burstein, S. H., Zurier, R. B. & Chen, J. D. Activation and binding of peroxisome proliferator-activated receptor γ by synthetic Cannabinoid ajulemic acid. Mol. Pharmacol. 63, 983-992 (2003). Cannabinoid-based drugs might function through mechanisms other than binding Cannabinoid receptors, such as through binding PPAR-γ, as described in this paper.
16. Piomelli, D. The molecular logic of endocannabinoid signalling. Nature Rev. Neurosci. 4, 873-884 (2003). Cannabinoids are best known for their psychoactive effects on the brain. This Review, together with references 28 and 29, discusses these mechanisms in detail.
17. Sugiura, T., Kobayashi, Y., Oka, S. & Waku, K. Biosynthesis and degradation of anandamide and 2-arachidonoylglycerol and their possible physiological significance. Prostaglandins Leukot. Essent. Fatty Acids 66, 173-192 (2002).
18. Devane, W. A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946-1949 (1992). An important breakthrough in the field was the discovery of an endocannabinoid. This paper describes the isolation of the first endocannabinoid to be found, AEA (previously known as anandamide).
19. Zygmunt, P. M. et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452-467 (1999).
20. Mechoulam, R. et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharm. 50, 83-90 (1995).
21. 1 receptor. Proc. Natl Acad. Sci. USA 98, 3662-3665 (2001).
22. Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C. & Bonner, T. I. Structure of cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561-564 (1990).
23. 2.
24. 2 receptor-mediated signalling: a focus on endocannabinoids. Prostaglandins Leukot. Essent. Fatty Acids 66, 161-171 (2002).
25. Klein, T. W. et al. The cannabinoid system and immune modulation. J. Leukoc. Biol. 74, 486-496 (2003).
26. Klein, T., Newton, C. & Friedman, H. Cannabinoid receptors and immunity. Immunol. Today 19, 373-381 (1998).
27. Berdyshev, E. V. Cannabinoid receptors and the regulation of immune response. Chem. Phys. Lipids 108, 169-190 (2000).
28. Schlicker, E. & Kathmann, M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol. Sci. 22, 565-572 (2001).
29. Christie, M. J. & Vaughan, C. W. Cannabinoids act backwards. Nature 410, 527-530 (2001).
30. Akira, S. & Takeda, K. Toll-like receptor signalling. Nature Rev. Immunol. 4, 499-511 (2004).
31. Noverr, M. C., Erb-Downward, J. R. & Huffnagle, G. B. Production of eicosanoids and other oxylipins by pathogenic eukaryotic microbes. Clin. Microbiol. Rev. 16, 517-533 (2003).
32. DiMarzo, V., DePetrocellis, L., Sepe, N. & Buono, A. Biosynthesis of anandamide and related acylethanolamides in mouse J774 macrophages and N18 neuroblastoma cells. Biochem. J. 316, 977-984 (1996).
33. DiMarzo, V. et al. Biosynthesis and inactivation of the endocannabinoid 2-arachidonoylglyceroi in circulating and tumoral macrophages. Eur. J. Biochem. 264, 258-267 (1999).
34. Maccarrone, M., Bari, M., Battista, N. & Finazzi-Agro, A. Endocannabinoid degradation, endotoxic shock and inflammation. Curr. Drug Targets Inflamm. Allergy 1, 53-63 (2002).
35. Matias, I. et al. Presence and regulation of the endocannabinoid system in human dendritic cells. Eur. J. Biochem. 269, 3771-3778 (2002).
36. Maccarrone, M. et al. Lipopolysaccharide downregulates fatty acid amide hydrolase expression and increases anandamide levels in human peripheral lymphocytes. Arch. Biochem. Biophys. 393, 321-328 (2001). References 32-36 discuss the metabolism of endocannabinoids in immune cells.
37. Wyss-Coray, T. & Mucke, L. Inflammation in neurodegenerative disease - a double-edged sword. Neuron 35, 419-432 (2002).
38. Moser, B., Wolf, M., Walz, A. & Loetscher, P. Chemokines: multiple levels of leukocyte migration control. Trends Immunol. 25, 75-84 (2004).
39. Oka, S. et al. 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, induces the migration of EoL-1 human eosinophilic leukemia cells and human peripheral blood eosinophils. J. Leukoc. Biol. 76, 1002-1009 (2004).
40. Rayman N. et al. Distinct expression profiles of the peripheral cannabinoid receptor in lymphoid tissues depending on receptor activation status. J. Immunol. 172, 2111-2117 (2004).
41. H1 response to a soluble protein. FASEB J. 18, 1914-1916 (2004).
42. 2, frequently expressed on AML blasts, either induces a neutrophilic differentiation block or confers abnormal migration properties in a ligand-dependent manner. Blood 104, 526-534 (2004). The many putative roles of cannabinoid receptors in immune-cell biology remain undefined. This paper indicates that these receptors might have a role in leukaemia.
43. Szabo, I. et al. Heterologous desensitization of opioid receptors by chemokines inhibits chemotaxis and enhances the perception of pain. Proc. Natl Acad. Sci. USA 99, 10276-10281 (2002).
44. 2 receptor mRNA in mouse immune cell subpopulations and following B cell stimulation. Eur. J. Pharmacol. 423, 235-241 (2001).
45. Daaka, Y., Friedman, H. & Klein, T. W. Cannabinoid receptor proteins are increased in Jurkat, human T-cell line after mftogen activation. J. Phamacol. Exp. Ther. 276, 776-783 (1996). This report was among the first to show that cannabinoid-receptor expression changes with variations in immune-cell activation.
46. 1 mRNA expression in mouse splenocytes. J. Neuroimmunol. 110, 161-167 (2000).
47. 2 receptor expression by TGF-β. Biochem. Biophys. Res. Commun. 290, 91-96 (2002).
48. 9-Tetrahydrocannabinol, cytokines and immunity to Legionalla pneumophila. Proc. Soc. Exp. Biol. Med. 209, 205-212 (1995).
49. 2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. Int. Immunopharmacol. 2, 69-82 (2002).
50. 2 has been reported to be expressed in the brain, this was the first report to indicate that it might be expressed by brain microglial cells.
51. Bromley, S. K. et al. The immunological synapse. Annu. Rev. Immunol. 19, 375-396 (2001).
52. 9- tetrahydrocannabinol on interferon production by murine spleen cells. Int. J. Immunopharmacol. 8, 819-824 (1986).
53. 9-Tetrahydrocannabinol decreases α/α interferon response to herpes simplex virus type 2 in the B6C3F1 mouse. Proc. Soc. Exp. Biol. Med. 181, 305-311 (1986).
54. Klein, T. W., Lane, B., Newton, C. A. & Friedman, H. The cannabinoid system and cytokine network. Proc. Soc. Exp. Biol. Med. 225, 1-8 (2000).
55. Smith, S. R., Terminelli, C. & Denhardt, G. Effects of cannabinoid receptor agonist and antagonist ligands on production of inflammatory cytokines and anti-inflammatory interleukin-10 in endotoxemic mice. J. Pharmacol. Exp. Ther. 293, 136-150 (2000).
56. Shohami, E., Gallily, R., Mechoulam, R., Bass, R. & Ben-Hur, T. Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNF-α inhibitor and an effective neuroprotectant J. Neuroimmunol. 72, 169-177 (1997). Using an animal model of closed head injury, this paper shows that non-psychoactive cannabinoids can suppress the production of pro-inflammatory cytokines.
57. Doble, A. The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol. Ther. 81, 163-221 (1999).
58. 2 receptor activation reduces mouse myocardial ischemia-reperfusion injury: inversement of cytokine/chemokines and PMN. J. Leukoc. Biol. 73, 453-459 (2004).
59. Baldwin, G. C. et al. Marijuana and cocaine impair alveolar macrophage function and cytokine production. Am. J. Respir. Crit. Care Med. 156, 1606-1613 (1997). This is one of the few reports that shows a direct suppressive effect of marijuana smoking on immune-cell function.
60. 9-Tetrahydrocannabinol injection induces cytokine-mediated mortality of mice infected with Legionella pneumophila. J. Pharmacol. Exp. Ther. 267, 635-640 (1993).
61. 9-Tetrahydrocannabinol enhances the secretion of interleukin 1 from endotoxin-stimulated macrophages. J. Pharmacol. Exp. Ther. 270, 1334-1339 (1994).
62. Smith, S. R., Terminelli, C. & Denhardt, G. Modulation of cytokine responses in Corynebacterium parvum-primed endotoxemic mice by centrally administered cannabinoid ligands. Eur. J. Pharmacol. 425, 73-83 (2001).
63. 2 receptor in cell differentiation. J. Biol. Chem. 275, 15621-15628 (2000).
64. Kishimoto, S. et al. 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, induces accelerated production of chemokines in HL-60 cells. J. Biochem. (Tokyo) 135, 517-524 (2004).
65. Pryce, G. et al. Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain 126, 2191-2202 (2003).
66. Ni, X. et al. WIN 55212-2, a cannabinoid receptor agonist, attenuates leukocyte/endothelial interactions in an experimental autoimmune encephalomyelitis model. Mult. Scler. 10, 158-164 (2004).
67. H1 cells induced by endothelial cell RANTES. J. Immunol. 163, 3269-3278 (1999).
68. Savinov, A. Y., Wong, F. S. & Chervonsky, A. V. IFN-γ affects homing of diabetogenic T cells. J. Immunol. 167, 6637-6643 (2001).
69. Cabral, G. & Dove Pettit, D. Drugs and immunity: cannabinoids and their role in decreased resistance to infectious diseases. J. Neuroimmunol. 83, 118-123 (1998).
70. H1-cell responses.
71. 9-Tetrahydrocannabinol treatment suppresses immunity and early IFNγ, IL-12, and IL-12 receptor β2 responses to Legionella pneumophila infection. J. Immunol. 164, 6461-6466 (2000).
72. Braun, M. C. & Kelsall, B. L. Regulation of interleukin-12 production by G-protein-coupled receptors. Microbes Infect. 3, 99-107 (2001).
73. 2 receptor-mediated, cytokine-dependent pathway. J. Immunol. 165, 373-380 (2000).
74. + regulatory T cells. Trends Immunol. 25, 374-380 (2004).
75. H3 regulatory cells. Immunol. Rev. 182, 207-214 (2001).
76. H2 cytokine balance in activated human T cells. J. Neuroimmunol. 133, 124-131 (2002).
77. H-cell responses.
78. Croxford, J. L. & Miller, S. D. Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R(+)WIN55,212. J. Clin. Invest. 111, 1231-1240 (2003).
79. Arevalo-Martin, A., Vela, J. M., Molina-Holgado, E., Borrell, J. & Guaza, C. Therapeutic action of cannabinoids in a murine model of multiple sclerosis. J. Neurosci. 23, 2511-2516 (2003).
80. H2 differentiation in allergic airway inflammation. Nature Immunol. 2, 45-50 (2001).
81. Klein, T. W. et al. Cannabinoid receptors and T helper biasing. J. Neuroimmunol. 147, 91-94 (2004).
82. Herring, A. C. & Kaminski, N. E. Cannabinol-mediated inhibition of nuclear factor-κB, cAMP response element-binding protein, and interleukin-2 secretion by activated thymocytes. J. Pharmacol. Exp. Ther. 291, 1156-1163 (1999).
83. Foulds, J., Burke, M., Steinberg, M., Williams, J. M. & Ziedonis, D. M. Advances in pharmacotherapy for tobacco dependence. Expert Opin. Emerg. Drugs 9, 39-53 (2004).
84. Howlett, A. C. et al. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology 47, 345-358 (2004).
85. 1 might have a role in controlling spasticity and tremor in individuals with multiple sclerosis, as shown in animals with chronic, relapsing EAE.
86. De Petrocellis, L. et al. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc. Natl Acad. Sci. USA 95, 8375-8380 (1998).
87. Galve-Roperh, I. et al. Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nature Med. 6, 313-319 (2000).
88. Bifulco, M. et al. A new strategy to block tumor growth by inhibiting endocannabinoid inactivation. FASEB J. 18, 1606-1608 (2004). In this paper, a novel mechanism is reported for endocannabinoids in the inhibition of tumour growth.
89. 9-Tetrahydrocannabinol: a novel treatment for experimental autoimmune encephalomyelitis. J. Neuroimmunol. 23, 73-81 (1989).
90. Wirguin, I. et al. Suppression of experimental autoimmune encephalomyelitis by cannabinoids. Immunopharmacology 28, 209-214 (1994).
91. 2. J. Leukoc. Biol. 76, 854-861 (2004).
92. Kingery, W. S. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain 73, 123-139 (1997).
93. Calignano, A., La Rana, G., Giuffrida, A. & Piomelli, D. Control of pain initiation by endogenous cannabinoids. Nature 394, 277-281 (1998).
94. 1.
95. Svendsen, K. B., Jensen, T. S. & Bach, F. W. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ 329, 253 (2004).
96. Baker, D. et al. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J. 15, 300-302 (2001).
97. Zajicek, J. et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 362, 1517-1526 (2003).
98. Vaney, C. et al. Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study. Mult. Scler. 10, 417-424 (2004).
99. Wade, D. T., Makela, P., Robson, P., House, H. & Bateman, C. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult. Scler. 10, 434-441 (2004).
100. Panikashvili, D. et al. An endogenous cannabinoid (2-AG) is neuroprotective after bran injury. Nature 413, 527-531 (2001).
101. Knoller, N. et al. Dexanabinol (HU-211) in the treatment of severe dosed head injury: a randomized, placebo-controlled, Phase II clinical trial. Crit. Care Med. 30, 548-554 (2002).
102. Pharmos Corporation. Dexanabinol did not demonstrate efficacy [online], http://www.pharmoscorp.com/news/pr/pr122004.html (2004).
103. Molina-Holgado, F. et al. Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia. J. Neurosci. 23, 6470-6474 (2003).
104. Manara, L. et al. Functional assessment of neuronal cannabinoid receptors in the muscular layers of human ileum and colon. Dig. Liver Dis. 34, 262-269 (2002).
105. 1-receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation. Br. J. Pharmacol. 134, 563-570 (2001).
106. Pinto, L. et al. Endocannabinoids as physiological regulators of colonic propulsion in mice. Gastroenterology 123, 227-234 (2002).
107. Mathison, R., Ho, W., Pittman, Q. J., Davison, J. S. & Sharkey, K. A. Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats. Br. J. Pharmacol. 142, 1247-1254 (2004).
108. Massa, F. et al. The endogenous cannabinoid system protects against colonic inflammation. J. Clin. Invest. 113, 1202-1209 (2004). The endocannabinoid system might control and regulate intestinal inflammatory responses, as reported in this paper.
109. 8-tetrahydrocannabinol-11-oic acid: a novel, orally effective cannabinoid with analgesic and anti-inflammatory properties. J. Pharmacol. Exp. Ther. 291, 31-38 (1999).
110. Zurier, R. B., Rossetti, R. G., Burstein, S. H. & Bidinger, B. Suppression of human monocyte interleukin-1β production by ajulemic acid, a nonpsychoactive cannabinoid. Biochem. Pharmacol. 65, 649-655 (2003).
111. Burstein, S. & Zurier, R. B. Pain reduction and lack of psychotropic effects with ajulemic acid. Arthritis Rheum. 50, 4078-4079 (2004).
112. Malfait, A. M. et al. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc. Natl Acad. Sci. USA 97, 9561-9566 (2000).
113. Gallily, R. et al. γ-Irradiation enhances apoptosis induced by cannabidiol, a non-psychotropic cannabinoid, in cultured HL-60 myeloblastic leukemia cells. Leuk. Lymphoma 44, 1767-1773 (2003).
114. Sumariwalla, P. F. et al. A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with antiinflammatory properties in murine collagen-induced arthritis. Arthritis Rheum. 50, 985-998 (2004). References 112-114 use animal models to show the anti-inflammatory potential of non-psychoactive cannabinoids.
115. Varga, K., Wagner, J. A., Bridgen, D. T. & Kunos, G. Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension. FASEB J. 12, 1035-1044 (1998).
116. Wang, Y. et al. Simultaneous measurement of anandamide and 2-arachidonoylglycerol by polymyxin B-selective adsorption and subsequent high-performance liquid chromatography analysis: increase in endogenous cannabinoids in the sera of patients with endotoxic shock. Anal. Biochem. 294, 73-82 (2001).
117. Gallily, R. et al. Protection against septic shock and suppression of tumor necrosis factor α and nitric oxide production by dexanabinol (HU-211), a nonpsychotropic cannabinoid. J. Pharmacol. Exp. Ther. 283, 918-924 (1997).
118. Veldhuis, W .B. et al. Neuroprotection by the endogenous cannabinoid anandamide and arvanil against in vivo excitotoxicity in the rat: role of vanilloid receptors and lipoxygenases. J. Neurosci. 23, 4127-4133 (2003).
119. Breivogel, C. S., Griffin, G., Di Marzo, V. & Martin, B. R. Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol. Pharmacol. 60, 155-163 (2001). This paper indicates that there might be more than two cannabinoid receptors.
120. Biswas, K. K. et al. Membrane cholesterol but not putative receptors mediates anandamide-induced hepatocyte apoptosis. Hepatology 38, 1167-1177 (2003). This paper shows that lipid rafts might be affected by cannabinoid-based drugs.
121. Vogt, A. B., Spindeldreher, S. & Kropshofer, H. Clustering of MHC-peptide complexes prior to their engagement in theimmunological synapse: lipid raft and tetraspan microdomans. Immunol. Rev. 189, 136-151 (2002).
122. 9-Tetrahydrocannabinol inhibitory of tumor necrosis factor-α: suppression of post-translational events. J. Pharm. Exp. Ther. 267, 1558-1565 (1993).
123. Chang, Y. H., Lee, S. T. & Lin, W. W. Effects of cannabinoids on LPS-stimulated inflammatory mediator release from macrophages: involvement of eicosanoids. J. Cell. Biochem. 81, 715-723 (2001).
124. Facchinetti, F., Del Giudice, E., Furegato, S., Passarotto, M. & Leon, A. Cannabinoids ablate release of TNFα in rat microglial cells stimulated with lipopolysaccharide. Glia 41, 161-168 (2003).