The AAPS Journal

, 11:109 | Cite as

Cannabinoids, Endocannabinoids, and Related Analogs in Inflammation

  • Sumner H. BursteinEmail author
  • Robert B. Zurier
NIDA Symposium: Drugs of Abuse: Drug Development and Cannabinoids


This review covers reports published in the last 5 years on the anti-inflammatory activities of all classes of cannabinoids, including phytocannabinoids such as tetrahydrocannabinol and cannabidiol, synthetic analogs such as ajulemic acid and nabilone, the endogenous cannabinoids anandamide and related compounds, namely, the elmiric acids, and finally, noncannabinoid components of Cannabis that show anti-inflammatory action. It is intended to be an update on the topic of the involvement of cannabinoids in the process of inflammation. A possible mechanism for these actions is suggested involving increased production of eicosanoids that promote the resolution of inflammation. This differentiates these cannabinoids from cyclooxygenase-2 inhibitors that suppress the synthesis of eicosanoids that promote the induction of the inflammatory process.

Key words

ajulemic acid cannabinoid elmiric acid endocannabinoid inflammation 



ajulemic acid


arachidonoyl glycerol










elmiric acid


fatty acid amidohydrolase


palmitoyl ethanolamide





This publication was made possible by grants DA17969, DA13691, and AI 056362 from the National Institutes of Health, Bethesda, MD. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.


  1. 1.
    S. H. Burstein. The cannabinoid acids: nonpsychoactive derivatives with therapeutic potential. Pharmacol. Ther. 82(1):87–96 (1999).PubMedGoogle Scholar
  2. 2.
    S. Burstein. The elmiric acids: biologically active anandamide analogs. Neuropharmacology. 55:1259–1264 (2007).PubMedGoogle Scholar
  3. 3.
    S. Burstein. Ajulemic acid (IP-751): synthesis, proof of principle, toxicity studies, and clinical trials. AAPS J. 7(1):E143–148 (2005).PubMedGoogle Scholar
  4. 4.
    R. B. Zurier. Prospects for cannabinoids as anti-inflammatory agents. J. Cell Biochem. 88(3):462–466 (2003).PubMedGoogle Scholar
  5. 5.
    J. Gertsch, M. Leonti, S. Raduner, I. Racz, J. Z. Chen, X. Q. Xie, K. H. Altmann, M. Karsak, and A. Zimmer. Beta-caryophyllene is a dietary cannabinoid. Proc. Natl. Acad. Sci. U. S. A. 105(26):9099–9104 (2008).PubMedGoogle Scholar
  6. 6.
    T. W. Klein, and G. A. Cabral. Cannabinoid-induced immune suppression and modulation of antigen-presenting cells. J Neuroimmune Pharmacol. 1(1):50–64 (2006).PubMedGoogle Scholar
  7. 7.
    T. W. Klein. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat. Rev. Immunol. 5(5):400–411 (2005).PubMedGoogle Scholar
  8. 8.
    T. W. Klein, and C. A. Newton. Therapeutic potential of cannabinoid-based drugs. Adv. Exp. Med. Biol. 601:395–413 (2007).PubMedGoogle Scholar
  9. 9.
    J. P. Buchweitz, P. W. Karmaus, K. J. Williams, J. R. Harkema, and N. E. Kaminski. Targeted deletion of cannabinoid receptors CB1 and CB2 produced enhanced inflammatory responses to influenza A/PR/8/34 in the absence and presence of Delta9-tetrahydrocannabinol. J. Leukoc. Biol. 83(3):785–796 (2008).PubMedGoogle Scholar
  10. 10.
    C. Fimiani, T. Liberty, A. J. Aquirre, I. Amin, N. Ali, and G. B. Stefano. Opiate, cannabinoid, and eicosanoid signaling converges on common intracellular pathways nitric oxide coupling. Prostaglandins Other Lipid Mediat. 57(1):23–34 (1999).PubMedGoogle Scholar
  11. 11.
    P. F. Sumariwalla, R. Gallily, S. Tchilibon, E. Fride, R. Mechoulam, and M. Feldmann. A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with antiinflammatory properties in murine collagen-induced arthritis. Arthritis Rheum. 50(3):985–998 (2004).PubMedGoogle Scholar
  12. 12.
    B. Costa, M. Colleoni, S. Conti, D. Parolaro, C. Franke, A. E. Trovato, and G. Giagnoni. Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn Schmiedebergs Arch. Pharmacol. 369(3):294–299 (2004).PubMedGoogle Scholar
  13. 13.
    B. Costa, A. E. Trovato, F. Comelli, G. Giagnoni, and M. Colleoni. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur. J. Pharmacol. 556(1–3):75–83 (2007).PubMedGoogle Scholar
  14. 14.
    G. Esposito, D. De Filippis, M. C. Maiuri, D. De Stefano, R. Carnuccio, and T. Iuvone. Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in beta-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-kappaB involvement. Neurosci. Lett. 399(1–2):91–95 (2006).PubMedGoogle Scholar
  15. 15.
    G. Esposito, C. Scuderi, C. Savani, L. Steardo Jr., D. De Filippis, P. Cottone, T. Iuvone, V. Cuomo, and L. Steardo. Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression. Br. J. Pharmacol. 151(8):1272–1279 (2007).PubMedGoogle Scholar
  16. 16.
    E. D. Giudice, L. Rinaldi, M. Passarotto, F. Facchinetti, A. D'Arrigo, A. Guiotto, M. D. Carbonare, L. Battistin, and A. Leon. Cannabidiol, unlike synthetic cannabinoids, triggers activation of RBL-2H3 mast cells. J. Leukoc. Biol. 81(6):1512–1522 (2007).PubMedGoogle Scholar
  17. 17.
    A. Thomas, G. L. Baillie, A. M. Phillips, R. K. Razdan, R. A. Ross, and R. G. Pertwee. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br. J. Pharmacol. 150(5):613–623 (2007).PubMedGoogle Scholar
  18. 18.
    D. McHugh, C. Tanner, R. Mechoulam, R. G. Pertwee, and R. A. Ross. Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2. Mol. Pharmacol. 73(2):441–450 (2008).PubMedGoogle Scholar
  19. 19.
    R. Capasso, F. Borrelli, G. Aviello, B. Romano, C. Scalisi, F. Capasso, and A. A. Izzo. Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice. Br. J. Pharmacol. 154(5):1001–1008 (2008).PubMedGoogle Scholar
  20. 20.
    S. Ben-Shabat, L. O. Hanus, G. Katzavian, and R. Gallily. New cannabidiol derivatives: synthesis, binding to cannabinoid receptor, and evaluation of their antiinflammatory activity. J. Med. Chem. 49(3):1113–1117 (2006).PubMedGoogle Scholar
  21. 21.
    M. Rajesh, P. Mukhopadhyay, S. Batkai, G. Hasko, L. Liaudet, J. W. Huffman, A. Csiszar, Z. Ungvari, K. Mackie, S. Chatterjee, and P. Pacher. CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. Am. J. Physiol. 293(4):H2210–2218 (2007).Google Scholar
  22. 22.
    E. Russo, and G. W. Guy. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med. Hypotheses. 66(2):234–246 (2006).PubMedGoogle Scholar
  23. 23.
    D. R. Blake, P. Robson, M. Ho, R. W. Jubb, and C. S. McCabe. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford, England). 45(1):50–52 (2006).Google Scholar
  24. 24.
    S. H. Burstein, M. Karst, U. Schneider, and R. B. Zurier. Ajulemic acid: a novel cannabinoid produces analgesia without a “high”. Life Sci. 75(12):1513–1522 (2004).PubMedGoogle Scholar
  25. 25.
    J. L. Wiley. Ajulemic acid. IDrugs. 8(12):1002–1011 (2005).PubMedGoogle Scholar
  26. 26.
    R. B. Zurier, R. G. Rossetti, J. H. Lane, J. M. Goldberg, S. A. Hunter, and S. H. Burstein. Dimethylheptyl-THC-11 oic acid: a nonpsychoactive antiinflammatory agent with a cannabinoid template structure. Arthritis Rheum. 41(1):163–170 (1998).PubMedGoogle Scholar
  27. 27.
    D. R. Johnson, J. A. Stebulis, R. G. Rossetti, S. H. Burstein, and R. B. Zurier. Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid. J. Cell Biochem. 100(1):184–190 (2007).PubMedGoogle Scholar
  28. 28.
    J. Parker, F. Atez, R. G. Rossetti, A. Skulas, R. Patel, and R. B. Zurier. Suppression of human macrophage interleukin-6 by a nonpsychoactive cannabinoid acid. Rheumatol. Int. 28(7):631–635 (2008).PubMedGoogle Scholar
  29. 29.
    J. A. Stebulis, D. R. Johnson, R. G. Rossetti, S. H. Burstein, and R. B. Zurier. Ajulemic acid, a synthetic cannabinoid acid, induces an antiinflammatory profile of eicosanoids in human synovial cells. Life Sci. 83(19–20):666–670 (2008) doi: 10.1016/j.lfs.2008.09.004.PubMedGoogle Scholar
  30. 30.
    R. B. Zurier, Y. -P. Sun, K. L. George, J. A. Stebulis, R. G. Rossetti, A. Skulas, E. Judge, C. N. Serhan. Ajulemic acid, a synthetic cannabinoid, increases formation of the endogenous proresolving and anti-inflammatory eicosanoid, lipoxin A4. FASEB J. (2009) doi: 10.1096/fj.08-118323.
  31. 31.
    A. Dyson, M. Peacock, A. Chen, J. P. Courade, M. Yaqoob, A. Groarke, C. Brain, Y. Loong, and A. Fox. Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat. Pain. 116(1–2):129–137 (2005).PubMedGoogle Scholar
  32. 32.
    A. Fox, and S. Bevan. Therapeutic potential of cannabinoid receptor agonists as analgesic agents. Expert. Opin. Investig. Drugs. 14(6):695–703 (2005).PubMedGoogle Scholar
  33. 33.
    R. E. Vann, C. D. Cook, B. R. Martin, and J. L. Wiley. Cannabimimetic properties of ajulemic acid. J. Pharmacol. Exp. Ther. 320(2):678–686 (2007).PubMedGoogle Scholar
  34. 34.
    V. A. Mitchell, S. Aslan, R. Safaei, and C. W. Vaughan. Effect of the cannabinoid ajulemic acid on rat models of neuropathic and inflammatory pain. Neurosci. Lett. 382(3):231–235 (2005).PubMedGoogle Scholar
  35. 35.
    M. Karst, K. Salim, S. Burstein, I. Conrad, L. Hoy, and U. Schneider. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA. 290(13):1757–1762 (2003).PubMedGoogle Scholar
  36. 36.
    A. L. Ambrosio, S. M. Dias, I. Polikarpov, R. B. Zurier, S. H. Burstein, and R. C. Garratt. Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor gamma. J. Biol. Chem. 282(25):18625–18633 (2007).PubMedGoogle Scholar
  37. 37.
    J. Liu, H. Li, S. H. Burstein, R. B. Zurier, and J. D. Chen. Activation and binding of peroxisome proliferator-activated receptor gamma by synthetic cannabinoid ajulemic acid. Mol. Pharmacol. 63(5):983–992 (2003).PubMedGoogle Scholar
  38. 38.
    A. L. Ambrosio, S. M. Dias, I. Polikarpov, R. B. Zurier, S. H. Burstein, and R. C. Garratt. Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor {gamma}. J. Biol. Chem. 282(25):18625–18633 (2007).PubMedGoogle Scholar
  39. 39.
    S. L. Teitelbaum, and F. P. Ross. Genetic regulation of osteoclast development and function. Nat. Rev. 4(8):638–649 (2003).Google Scholar
  40. 40.
    K. L. George, L. H. Saltman, G. S. Stein, J. B. Lian, and R. B. Zurier. Ajulemic acid, a nonpsychoactive cannabinoid acid, suppresses osteoclastogenesis in mononuclear precursor cells and induces apoptosis in mature osteoclast-like cells. J. Cell Physiol. 214(3):714–720 (2008).PubMedGoogle Scholar
  41. 41.
    R. Q. Skrabek, L. Galimova, K. Ethans, and D. Perry. Nabilone for the treatment of pain in fibromyalgia. J. Pain. 9(2):164–173 (2008).PubMedGoogle Scholar
  42. 42.
    P. Beaulieu, and M. Ware. Reassessment of the role of cannabinoids in the management of pain. Curr. Opin. Anaesthesiol. 20(5):473–477 (2007).PubMedGoogle Scholar
  43. 43.
    P. Beaulieu. Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can. J. Anaesth. 53(8):769–775 (2006).PubMedCrossRefGoogle Scholar
  44. 44.
    C. A. Lunn, J. S. Fine, A. Rojas-Triana, J. V. Jackson, X. Fan, T. T. Kung, W. Gonsiorek, M. A. Schwarz, B. Lavey, J. A. Kozlowski, S. K. Narula, D. J. Lundell, R. W. Hipkin, and L. A. Bober. A novel cannabinoid peripheral cannabinoid receptor-selective inverse agonist blocks leukocyte recruitment in vivo. J. Pharmacol. Exp. Ther. 316(2):780–788 (2006).PubMedGoogle Scholar
  45. 45.
    E. Selvi, S. Lorenzini, E. Garcia-Gonzalez, R. Maggio, P. E. Lazzerini, P. L. Capecchi, E. Balistreri, A. Spreafico, S. Niccolini, G. Pompella, M. R. Natale, F. Guideri, F. Laghi Pasini, M. Galeazzi, and R. Marcolongo. Inhibitory effect of synthetic cannabinoids on cytokine production in rheumatoid fibroblast-like synoviocytes. Clin. Exp. Rheumatol. 26(4):574–581 (2008).PubMedGoogle Scholar
  46. 46.
    E. C. Mbvundula, R. A. Bunning, and K. D. Rainsford. Effects of cannabinoids on nitric oxide production by chondrocytes and proteoglycan degradation in cartilage. Biochem. Pharmacol. 69(4):635–640 (2005).PubMedGoogle Scholar
  47. 47.
    L. Giannini, S. Nistri, R. Mastroianni, L. Cinci, A. Vannacci, C. Mariottini, M. B. Passani, P. F. Mannaioni, D. Bani, and E. Masini. Activation of cannabinoid receptors prevents antigen-induced asthma-like reaction in guinea pigs. J. Cell. Mol. Med. 12(6A):2381–2394 (2008).PubMedGoogle Scholar
  48. 48.
    J. C. Ashton, J. L. Wright, J. M. McPartland, and J. D. Tyndall. Cannabinoid CB1 and CB2 receptor ligand specificity and the development of CB2-selective agonists. Curr. Med. Chem. 15(14):1428–1443 (2008).PubMedGoogle Scholar
  49. 49.
    D. G. Deutsch, N. Ueda, and S. Yamamoto. The fatty acid amide hydrolase (FAAH). Prostaglandins Leukot. Essent. Fatty Acids. 66(2–3):201–210 (2002).PubMedGoogle Scholar
  50. 50.
    A. Giuffrida, M. Beltramo, and D. Piomelli. Mechanisms of endocannabinoid inactivation: biochemistry and pharmacology. J. Pharmacol. Exp. Ther. 298(1):7–14 (2001).PubMedGoogle Scholar
  51. 51.
    R. A. Puffenbarger. Molecular biology of the enzymes that degrade endocannabinoids. Curr. Drug Targets CNS Neurol. Disord. 4(6):625–631 (2005).PubMedGoogle Scholar
  52. 52.
    N. Ueda, K. Tsuboi, and D. M. Lambert. A second N-acylethanolamine hydrolase in mammalian tissues. Neuropharmacology. 48(8):1079–1085 (2005).PubMedGoogle Scholar
  53. 53.
    A. Giuffrida, and D. Piomelli. The endocannabinoid system: a physiological perspective on its role in psychomotor control. Chem. Phys. Lipids. 108(1–2):151–158 (2000).PubMedGoogle Scholar
  54. 54.
    H. Schuel, L. J. Burkman, J. Lippes, K. Crickard, E. Forester, D. Piomelli, and A. Giuffrida. N-Acylethanolamines in human reproductive fluids. Chem. Phys. Lipids. 121(1–2):211–227 (2002).PubMedGoogle Scholar
  55. 55.
    G. Kunos, Z. Jarai, K. Varga, J. Liu, L. Wang, and J. A. Wagner. Cardiovascular effects of endocannabinoids—the plot thickens. Prostaglandins Other Lipid Mediat. 61(1–2):71–84 (2000).PubMedGoogle Scholar
  56. 56.
    A. H. Lichtman, S. A. Varvel, and B. R. Martin. Endocannabinoids in cognition and dependence. Prostaglandins Leukot. Essent. Fatty Acids. 66(2–3):269–285 (2002).PubMedGoogle Scholar
  57. 57.
    M. Maccarrone, K. Falciglia, M. Di Rienzo, and A. Finazzi-Agro. Endocannabinoids, hormone-cytokine networks and human fertility. Prostaglandins Leukot. Essent. Fatty Acids. 66(2–3):309–317 (2002).PubMedGoogle Scholar
  58. 58.
    E. Murillo-Rodríguez, M. Sánchez-Alavez, L. Navarro, D. Martínez-González, R. Drucker-Colín, and O. Prospéro-García. Anandamide modulates sleep and memory in rats. Brain Res. 812(1–2):270–274 (1998).PubMedGoogle Scholar
  59. 59.
    D. Parolaro, P. Massi, T. Rubino, and E. Monti. Endocannabinoids in the immune system and cancer. Prostaglandins Leukot. Essent. Fatty Acids. 66(2–3):319–332 (2002).PubMedGoogle Scholar
  60. 60.
    J. M. Walker, and S. M. Huang. Endocannabinoids in pain modulation. Prostaglandins Leukot. Essent. Fatty Acids. 66(2–3):235–242 (2002).PubMedGoogle Scholar
  61. 61.
    A. C. Howlett, and S. Mukhopadhyay. Cellular signal transduction by anandamide and 2-arachidonoylglycerol. Chem. Phys. Lipids. 108(1–2):53–70 (2000).PubMedGoogle Scholar
  62. 62.
    H. B. Bradshaw, N. Rimmerman, J. F. Krey, and J. M. Walker. Sex and hormonal cycle differences in rat brain levels of pain-related cannabimimetic lipid mediators. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291(2):R349–358 (2006).PubMedGoogle Scholar
  63. 63.
    H. B. Bradshaw, and J. M. Walker. The expanding field of cannabimimetic and related lipid mediators. Br. J. Pharmacol. 144(4):459–465 (2005).PubMedGoogle Scholar
  64. 64.
    L. De Petrocellis, D. Melck, T. Bisogno, and V. Di Marzo. Endocannabinoids and fatty acid amides in cancer, inflammation and related disorders. Chem. Phys. Lipids. 108(1–2):191–209 (2000).PubMedGoogle Scholar
  65. 65.
    H. Schwarz, F. J. Blanco, and M. Lotz. Anadamide, an endogenous cannabinoid receptor agonist inhibits lymphocyte proliferation and induces apoptosis. J. Neuroimmunol. 55(1):107–115 (1994).PubMedGoogle Scholar
  66. 66.
    M. Maccarrone, T. Lorenzon, M. Bari, G. Melino, and A. Finazzi-Agro. Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors. J. Biol. Chem. 275(41):31938–31945 (2000).PubMedGoogle Scholar
  67. 67.
    C. E. Rockwell, N. T. Snider, J. T. Thompson, J. P. Vanden Heuvel, and N. E. Kaminski. Interleukin-2 suppression by 2-arachidonyl glycerol is mediated through peroxisome proliferator activated receptor{gamma} independently of cannabinoid receptors 1 and 2. Mol. Pharmacol. 70(1):101–111 (2006).PubMedGoogle Scholar
  68. 68.
    B. L. Kaplan, Y. Ouyang, A. Herring, S. S. Yea, R. Razdan, and N. E. Kaminski. Inhibition of leukocyte function and interleukin-2 gene expression by 2-methylarachidonyl-(2′-fluoroethyl)amide, a stable congener of the endogenous cannabinoid receptor ligand anandamide. Toxicol. Appl. Pharmacol. 205(2):107–115 (2005).PubMedGoogle Scholar
  69. 69.
    B. L. Kaplan, Y. Ouyang, C. E. Rockwell, G. K. Rao, and N. E. Kaminski. 2-Arachidonoyl-glycerol suppresses interferon-gamma production in phorbol ester/ionomycin-activated mouse splenocytes independent of CB1 or CB2. J. Leukoc. Biol. 77(6):966–974 (2005).PubMedGoogle Scholar
  70. 70.
    C. E. Rockwell, and N. E. Kaminski. A cyclooxygenase metabolite of anandamide causes inhibition of interleukin-2 secretion in murine splenocytes. J. Pharmacol. Exp. Ther. 311(2):683–690 (2004).PubMedGoogle Scholar
  71. 71.
    J. Li, N. E. Kaminski, and D. H. Wang. Anandamide-induced depressor effect in spontaneously hypertensive rats: role of the vanilloid receptor. Hypertension. 41(3 Pt 2):757–762 (2003).PubMedGoogle Scholar
  72. 72.
    D. Centonze, M. Bari, S. Rossi, C. Prosperetti, R. Furlan, F. Fezza, V. De Chiara, L. Battistini, G. Bernardi, S. Bernardini, G. Martino, and M. Maccarrone. The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis. Brain. 130(Pt 10):2543–2553 (2007).PubMedGoogle Scholar
  73. 73.
    D. Centonze, A. Finazzi-Agro, G. Bernardi, and M. Maccarrone. The endocannabinoid system in targeting inflammatory neurodegenerative diseases. Trends Pharmacol. Sci. 28(4):180–187 (2007).PubMedGoogle Scholar
  74. 74.
    J. LoVerme, G. La Rana, R. Russo, A. Calignano, and D. Piomelli. The search for the palmitoylethanolamide receptor. Life Sci. 77(14):1685–1698 (2005).PubMedGoogle Scholar
  75. 75.
    G. Re, R. Barbero, A. Miolo, and V. Di Marzo. Palmitoylethanolamide, endocannabinoids and related cannabimimetic compounds in protection against tissue inflammation and pain: potential use in companion animals. Vet. J. 173(1):21–30 (2007).PubMedGoogle Scholar
  76. 76.
    M. Dalle Carbonare, E. Del Giudice, A. Stecca, D. Colavito, M. Fabris, A. D'Arrigo, D. Bernardini, M. Dam, and A. Leon. A saturated N-acylethanolamine other than N-palmitoyl ethanolamine with anti-inflammatory properties: a neglected story. J. Neuroendocrinol. 20(Suppl 1):26–34 (2008).PubMedGoogle Scholar
  77. 77.
    L. E. Wise, R. Cannavacciulo, B. F. Cravatt, B. F. Martin, and A. H. Lichtman. Evaluation of fatty acid amides in the carrageenan-induced paw edema model. Neuropharmacology. 54(1):181–188 (2008).PubMedGoogle Scholar
  78. 78.
    G. D'Argenio, S. Petrosino, C. Gianfrani, M. Valenti, G. Scaglione, I. Grandone, S. Nigam, I. Sorrentini, G. Mazzarella, and V. Di Marzo. Overactivity of the intestinal endocannabinoid system in celiac disease and in methotrexate-treated rats. J. Mol. Med. (Berlin, Germany). 85(5):523–530 (2007).Google Scholar
  79. 79.
    Y. Avraham, I. Magen, O. Zolotarev, L. Vorobiav, A. Nachmias, O. Pappo, Y. Ilan, E. M. Berry, and Z. Ackerman. 2-Arachidonoylglycerol, an endogenous cannabinoid receptor agonist, in various rat tissues during the evolution of experimental cholestatic liver disease. Prostaglandins Leukot. Essent. Fatty Acids. 79(1–2):35–40 (2008).PubMedGoogle Scholar
  80. 80.
    F. Massa, G. Marsicano, H. Hermann, A. Cannich, K. Monory, B. F. Cravatt, G. L. Ferri, A. Sibaev, M. Storr, and B. Lutz. The endogenous cannabinoid system protects against colonic inflammation. J. Clin. Invest. 113(8):1202–1209 (2004).PubMedGoogle Scholar
  81. 81.
    Y. Nakajima, Y. Furuichi, K. K. Biswas, T. Hashiguchi, K. Kawahara, K. Yamaji, T. Uchimura, Y. Izumi, and I. Maruyama. Endocannabinoid, anandamide in gingival tissue regulates the periodontal inflammation through NF-kappaB pathway inhibition. FEBS Lett. 580(2):613–619 (2006).PubMedGoogle Scholar
  82. 82.
    J. Zhang, and C. Chen. Endocannabinoid 2-arachidonoylglycerol protects neurons by limiting COX-2 elevation. J. Biol. Chem. 283(33):22601–22611 (2008).PubMedGoogle Scholar
  83. 83.
    R. Sancho, M. A. Calzado, V. Di Marzo, G. Appendino, and E. Munoz. Anandamide inhibits nuclear factor-kappaB activation through a cannabinoid receptor-independent pathway. Mol. Pharmacol. 63(2):429–438 (2003).PubMedGoogle Scholar
  84. 84.
    S. M. Huang, T. Bisogno, T. J. Petros, S. Y. Chang, P. A. Zavitsanos, R. E. Zipkin, R. Sivakumar, A. Coop, D. Y. Maeda, L. De Petrocellis, S. Burstein, V. Di Marzo, and J. M. Walker. Identification of a new class of molecules, the arachidonyl amino acids, and characterization of one member that inhibits pain. J. Biol. Chem. 276(46):42639–42644 (2001).PubMedGoogle Scholar
  85. 85.
    S. M. A. Burstein, W. Pearson, T. Rooney, B. Yagen, R. Zipkin, A. Zurier. Symposium on Cannabinoids, pp 31 (1997).Google Scholar
  86. 86.
    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(21):12198–12203 (1999).PubMedGoogle Scholar
  87. 87.
    R. G. Pertwee. Cannabinoid receptors and pain. Prog. Neurobiol. 63(5):569–611 (2001).PubMedGoogle Scholar
  88. 88.
    R. G. Pertwee. The ring test: a quantitative method for assessing the ‘cataleptic’ effect of cannabis in mice. Br. J. Pharmacol. 46(4):753–763 (1972).PubMedGoogle Scholar
  89. 89.
    T. Sheskin, L. Hanus, J. Slager, Z. Vogel, and R. Mechoulam. Structural requirements for binding of anandamide-type compounds to the brain cannabinoid receptor. J. Med. Chem. 40(5):659–667 (1997).PubMedGoogle Scholar
  90. 90.
    C. R. Hiley, and S. S. Kaup. GPR55 and the vascular receptors for cannabinoids. Br. J. Pharmacol. 152(5):559–561 (2007).PubMedGoogle Scholar
  91. 91.
    D. G. Johns, D. J. Behm, D. J. Walker, Z. Ao, E. M. Shapland, D. A. Daniels, M. Riddick, S. Dowell, P. C. Staton, P. Green, U. Shabon, W. Bao, N. Aiyar, T. L. Yue, A. J. Brown, A. D. Morrison, and S. A. Douglas. The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects. Br. J. Pharmacol. 152(5):825–831 (2007).PubMedGoogle Scholar
  92. 92.
    S. Oka, K. Nakajima, A. Yamashita, S. Kishimoto, and T. Sugiura. Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem. Biophys. Res. Commun. 362(4):928–934 (2007).PubMedGoogle Scholar
  93. 93.
    A. L. Wiles, R. J. Pearlman, M. Rosvall, K. R. Aubrey, and R. J. Vandenberg. N-Arachidonyl-glycine inhibits the glycine transporter, GLYT2a. J. Neurochem. 99:781–786 (2006).PubMedGoogle Scholar
  94. 94.
    Z. Yang, K. R. Aubrey, I. Alroy, R. J. Harvey, R. J. Vandenberg, and J. W. Lynch. Subunit-specific modulation of glycine receptors by cannabinoids and N-arachidonyl-glycine. Biochem. Pharmacol. 76(8):1014–1023 (2008).PubMedGoogle Scholar
  95. 95.
    L. C. Samuelson, L. J. Swanberg, and I. Gantz. Mapping of the novel G protein-coupled receptor Gpr18 to distal mouse chromosome 14. Mamm. Genome. 7(12):920–921 (1996).PubMedGoogle Scholar
  96. 96.
    M. Kohno, H. Hasegawa, A. Inoue, M. Muraoka, T. Miyazaki, K. Oka, and M. Yasukawa. Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18. Biochem. Biophys. Res. Commun. 347(3):827–832 (2006).PubMedGoogle Scholar
  97. 97.
    Y. Oh da, J. M. Yoon, M. J. Moon, J. I. Hwang, H. Choe, J. Y. Lee, J. I. Kim, S. Kim, H. Rhim, D. K. O'Dell, J. M. Walker, H. S. Na, M. G. Lee, H. B. Kwon, K. Kim, and J. Y. Seong. Identification of farnesyl pyrophosphate and N-arachidonylglycine as endogenous ligands for GPR92. J. Biol. Chem. 283(30):21054–21064 (2008).PubMedGoogle Scholar
  98. 98.
    J. J. Prusakiewicz, P. J. Kingsley, K. R. Kozak, and L. J. Marnett. Selective oxygenation of N-arachidonylglycine by cyclooxygenase-2. Biochem. Biophys. Res. Commun. 296(3):612–617 (2002).PubMedGoogle Scholar
  99. 99.
    H. B. Bradshaw, E. Verfring, J. A. Jahnsen, O'Dell, S. Burstein, M. J. Walker. ICRS Symposium on Cannabinoids, Clearwater, FL, (2005).Google Scholar
  100. 100.
    G. Milman, Y. Maor, S. Abu-Lafi, M. Horowitz, R. Gallily, S. Batkai, F. M. Mo, L. Offertaler, P. Pacher, G. Kunos, and R. Mechoulam. N-arachidonoyl L-serine, an endocannabinoid-like brain constituent with vasodilatory properties. Proc. Natl. Acad. Sci. U. S. A. 103(7):2428–2433 (2006).PubMedGoogle Scholar
  101. 101.
    J. C. Sipe, N. Arbour, A. Gerber, and E. Beutler. Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders. J. Leukoc. Biol. 78(1):231–238 (2005).PubMedGoogle Scholar
  102. 102.
    S. H. Burstein, J. K. Adams, H. B. Bradshaw, C. Fraioli, R. G. Rossetti, R. A. Salmonsen, J. W. Shaw, J. M. Walker, R. E. Zipkin, and R. B. Zurier. Potential anti-inflammatory actions of the elmiric (lipoamino) acids. Bioorg. Med. Chem. 15(10):3345–3355 (2007).PubMedGoogle Scholar
  103. 103.
    B. F. Cravatt, K. Demarest, M. P. Patricelli, M. H. Bracey, D. K. Giang, B. 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(16):9371–9376 (2001).PubMedGoogle Scholar
  104. 104.
    M. Cascio, A. Minassi, A. Ligresti, G. Appendino, S. Burstein, and V. Di Marzo. A structure-activity relationship study on N-arachidonoyl-amino acids as possible endogenous inhibitors of fatty acid amide hydrolase. Biochem. Biophys. Res. Commun. 314(1):192–196 (2004).Google Scholar
  105. 105.
    L. C. Bell-Parikh, T. Ide, J. A. Lawson, P. McNamara, M. Reilly, and G. A. FitzGerald. Biosynthesis of 15-deoxy-delta12,14-PGJ2 and the ligation of PPARgamma. J. Clin. Invest. 112(6):945–955 (2003).PubMedGoogle Scholar
  106. 106.
    S. R. Smith, G. Denhardt, and C. Terminelli. The anti-inflammatory activities of cannabinoid receptor ligands in mouse peritonitis models. Eur. J. Pharmacol. 432(1):107–119 (2001).PubMedGoogle Scholar
  107. 107.
    C. A. Audette, and S. Burstein. Inhibition of leukocyte adhesion by the in vivo and in vitro administration of cannabinoids. Life Sci. 47(9):753–759 (1990).PubMedGoogle Scholar
  108. 108.
    S. H. Burstein, C. A. Audette, S. A. Doyle, K. Hull, S. A. Hunter, and V. Latham. Antagonism to the actions of platelet activating factor by a nonpsychoactive cannabinoid. J. Pharmacol. Exp. Ther. 251(2):531–535 (1989).PubMedGoogle Scholar
  109. 109.
    S. Burstein, S. A. Hunter, K. Ozman, and L. Renzulli. Prostaglandins and cannabis—XIII. Cannabinoid-induced elevation of lipoxygenase products in mouse peritoneal macrophages. Biochem. Pharmacol. 33(16):2653–2656 (1984).PubMedGoogle Scholar
  110. 110.
    S. Burstein. Cannabinoid induced changes in eicosanoid synthesis by mouse peritoneal cells. Adv. Exp. Med. Biol. 288:107–112 (1991).PubMedGoogle Scholar
  111. 111.
    R. Succar, V. A. Mitchell, and C. W. Vaughan. Actions of N-arachidonyl-glycine in a rat inflammatory pain model. Mol. Pain. 3(1):24 (2007).PubMedGoogle Scholar
  112. 112.
    L. A. Vuong, V. A. Mitchell, and C. W. Vaughan. Actions of N-arachidonyl-glycine in a rat neuropathic pain model. Neuropharmacology. 54(1):189–193 (2008).PubMedGoogle Scholar
  113. 113.
    S. Burstein, and R. Salmonsen. Acylamido analogs of endocannabinoids selectively inhibit cancer cell proliferation. Bioorg. Med. Chem. 16(22):9644–9651 (2008).PubMedGoogle Scholar
  114. 114.
    M. L. Barrett, D. Gordon, and F. J. Evans. Isolation from Cannabis sativa L. of cannflavin—a novel inhibitor of prostaglandin production. Biochem. Pharmacol. 34(11):2019–2024 (1985).PubMedGoogle Scholar
  115. 115.
    M. L. Barrett, A. M. Scutt, and F. J. Evans. Cannflavin A and B, prenylated flavones from Cannabis sativa L. Experientia. 42(4):452–453 (1986).PubMedGoogle Scholar
  116. 116.
    R. D. Sofia, S. D. Nalepa, H. B. Vassar, and L. C. Knobloch. Comparative anti-phlogistic activity of delta 9-tetrahydrocannabinol, hydrocortisone and aspirin in various rat paw edema models. Life Sci. 15(2):251–260 (1974).PubMedGoogle Scholar
  117. 117.
    S. Burstein, C. Varanelli, and L. T. Slade. Prostaglandins and cannabis—III. Inhibition of biosynthesis by essential oil components of marihuana. Biochem. Pharmacol. 24(9):1053–1054 (1975).PubMedGoogle Scholar
  118. 118.
    R. K. Razdan. Structure-activity relationships in cannabinoids. Pharmacol. Rev. 38(2):75–149 (1986).PubMedGoogle Scholar
  119. 119.
    S. Hougee, A. Sanders, J. Faber, Y. M. Graus, W. B. van den Berg, J. Garssen, H. F. Smit, and M. A. Hoijer. Decreased pro-inflammatory cytokine production by LPS-stimulated PBMC upon in vitro incubation with the flavonoids apigenin, luteolin or chrysin, due to selective elimination of monocytes/macrophages. Biochem. Pharmacol. 69(2):241–248 (2005).PubMedGoogle Scholar
  120. 120.
    A. M. Lehane, and K. J. Saliba. Common dietary flavonoids inhibit the growth of the intraerythrocytic malaria parasite. BMC Res. Notes. 1:26 (2008).PubMedGoogle Scholar
  121. 121.
    P. Ashokkumar, and G. Sudhandiran. Protective role of luteolin on the status of lipid peroxidation and antioxidant defense against azoxymethane-induced experimental colon carcinogenesis. Biomed. Pharmacother. 62(9):590–597 (2008).PubMedGoogle Scholar
  122. 122.
    L. Hui-Lin. The origin and use of cannabis in Eastern Asia. In V. Rubin (ed.), Cannabis and Culture, Mouton, The Hague, 1975.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2009

Authors and Affiliations

  1. 1.Department of Biochemistry & Molecular PharmacologyUniversity of Massachusetts Medical SchoolWorcesterUSA
  2. 2.Department of MedicineUniversity of Massachusetts Medical SchoolWorcesterUSA

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