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The AAPS Journal

, Volume 7, Issue 3, pp E625–E654 | Cite as

The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids

  • Roger G. PertweeEmail author
Article
  • 521 Downloads

Abstract

There are at least 2 types of cannabinoid receptor, CB1 and CB2, both G protein coupled. CB1 receptors are expressed predominantly at nerve terminals and mediate inhibition of transmitter release, whereas CB2 receptors are found mainly on immune cells, their roles including the modulation of cytokine release and of immune cell migration. Endogenous agonists for cannabinoid receptors also exist. These “endocannabinoids” are synthesized on demand and removed from their sites of action by cellular uptake and intracellular enzymic hydrolysis. Endocannabinoids and their receptors together constitute the endocannabinoid system. This review summarizes evidence that there are certain central and peripheral disorders in which increases take place in the release of endocannabinoids onto their receptors and/or in the density or coupling efficiency of these receptors and that this upregulation is protective in some disorders but can have undesirable consequences in others. It also considers therapeutic strategies by which this upregulation might be modulated to clinical advantage. These strategies include the administration of (1) a CB1 and/or CB2 receptor agonist or antagonist that does or does not readily cross the blood brain barrier; (2) a CB1 and/or CB2 receptor agonist intrathecally or directly to some other site outside the brain; (3) a partial CB1 and/or CB2 receptor agonist rather than a full agonist; (4) a CB1 and/or CB2 receptor agonist together with a noncannabinoid, for example, morphine or codeine; (5) an inhibitor or activator of endocannabinoid biosynthesis, cellular uptake, or metabolism; (6) an allosteric modulator of the CB1 receptor; and (7) a CB2 receptor inverse agonist.

KeyWords

cannabinoid receptors endocannabinoids fatty acid amide hydrolase inhibitors autoprotection therapeutic strategies 

References

  1. 1.
    Howlett AC, Barth F, Bonner TI, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors.Pharmacol Rev. 2002;54:161–202.CrossRef
  2. 2.
    Pertwee RG. Pharmacological actions of cannabinoids. In: Pertwee RG, ed.Cannabinoids, Handbook of Experimental Pharmacology. Heidelberg, Germany: Springer-Verlag; 2005;168:1–51.
  3. 3.
    Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA.Nature. 1990;346:561–564.CrossRef
  4. 4.
    Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids.Nature. 1993;365:61–65.CrossRef
  5. 5.
    Pertwee RG. Pharmacology of cannabinoid receptor ligands.Curr Med Chem. 1999;6:635–664.
  6. 6.
    Pertwee RG. Inverse agonism and neutral antagonism at cannabinoid CB1 receptors.Life Sci. 2005;76:1307–1324.CrossRef
  7. 7.
    Pertwee RG. Novel pharmacological targets for cannabinoids.Curr Neuropharmacol. 2004;2:9–29.CrossRef
  8. 8.
    Price MRBaillie GThomas A. Allosteric modulation of the cannabinoid CB1 receptor.Mol Pharmacol. In press.
  9. 9.
    Bradshaw HB, Walker JM. The expanding field of cannabimimetic and related lipid mediators.Br J Pharmacol. 2005;144:459–465.CrossRef
  10. 10.
    Steffens M, Zentner J, Honegger J, Feuerstein TJ. Binding affinity and agonist activity of putative endogenous cannabinoids at the human neocortical CB1 receptor.Biochem Pharmacol. 2005;69:169–178.CrossRef
  11. 11.
    Cabral GA, Staab A. Effects on the immune system. In: Pertwee RG, ed.Cannabinoids, Handbook of Experimental Pharmacology. Heidelberg, Germany: Springer-Verlag; 2005;168:385–423.
  12. 12.
    Szabo B, Schlicker E. Effects of cannabinoids on neurotransmission. In: Pertwee RG, ed.Cannabinoids, Handbook of Experimental Pharmacology. Heidelberg, Germany: Springer-Verlag; 2005;168:327–365.
  13. 13.
    Vaughan CW, Christie MJ. Retrograde signalling by endocannabinoids. In: Pertwee RG, ed.Cannabinoids, Handbook of Experimental Pharmacology. Heidelberg, Germany: Springer-Verlag; 2005;168:367–383.
  14. 14.
    Price TJ, Patwardhan A, Akopian AN, Hargreaves KM, Flores CM. Modulation of trigeminal sensory neuron activity by the dual cannabinoid-vanilloid agonists anandamide,N-arachidonoyl-dopamine and arachidonyl-2-chloroethylamide.Br J Pharmacol. 2004;141:1118–1130.CrossRef
  15. 15.
    Baker CL, McDougall JJ. The cannabinomimetic arachidonyl-2-chloroethylamide (ACEA) acts on capsaicin-sensitive TRPV1 receptors but not cannabinoid receptors in rat joints.Br J Pharmacol. 2004;142:1361–1367.CrossRef
  16. 16.
    Di Marzo V, De Petrocellis L, Bisogno T. The biosynthesis, fate and pharmacological properties of endocannabinoids. In: Pertwee RG, ed.Camabinoids, Handbook of Experimental Pharmacology. Heidelberg, Germany: Springer-Verlag; 2005;168:147–185.
  17. 17.
    Bisogno T, Melck D, Bobrov MY, et al.N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activityin vitro andin vivo.Biochem J. 2000;351:817–824.CrossRef
  18. 18.
    Leggett JD, Aspley S, Beckett SRG, D’Antona AM, Kendall DA, Kendall DA. Oleamide is a selective endogenous agonist of rat and human CB1 cannabinoid receptors.Br J Pharmacol. 2004;141:253–262.CrossRef
  19. 19.
    Porter AC, Sauer J-M, Knierman MD, et al. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor.J Pharmacol Exp Ther. 2002;301:1020–1024.CrossRef
  20. 20.
    Cravatt BF, Lichtman AH. The endogenous cannabinoid system and its role in nociceptive behavior.J Neurobiol. 2004;61:149–160.CrossRef
  21. 21.
    Hillard CJ, Jarrahian A. Cellular accumulation of anandamide: consensus and controversy.Br J Pharmacol. 2003;140:802–808.CrossRef
  22. 22.
    Ueda N. Endocannabinoid hydrolases.Prostaglandins Other Lipid Mediat. 2002;68–9:521–534.CrossRef
  23. 23.
    Ho W-SV, Hillard CJ. Modulators of endocannabinoid enzymic hydrolysis and membrane transport. In: Pertwee RG, ed.Cannabinoids, Handbook of Experimental Pharmacology. Heidelberg, Germany: Springer-Verlag; 2005;168:187–207.
  24. 24.
    Gulyas AI, Cravatt BF, Bracey MH, et al. Segregation of 2 endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala.Eur J Neurosci. 2004;20:441–458.CrossRef
  25. 25.
    Ueda N, Yamanaka K, Yamamoto S. Purification and characterization of an acid amidase selective forN-palmitoylethanolamine, a putative endogenous anti-inflammatory substance.J Biol Chem. 2001;276:35552–35557.CrossRef
  26. 26.
    Lo Verme J, Gaetani S, Fu J, Oveisi F, Burton K, Piomelli D. Regulation of food intake by oleoylethanolamide.Cell Mol Life Sci. 2005;62:708–716.CrossRef
  27. 27.
    Fegley D, Gaetani S, Duranti A, et al. Characterization of the fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB597): effects on anandamide and oleoylethanolamide deactivation.J Pharmacol Exp Ther. 2005;313:352–358.CrossRef
  28. 28.
    Kozak KR, Marnett LJ. Oxidative metabolism of endocannabinoids.Prostaglandins Leukot Essent Fatty Acids. 2002;66:211–220.CrossRef
  29. 29.
    Saario SM, Savinainen JR, Laitinen JT, Järvinen T, Niemi R. Monoglyceride lipase-like enzymatic activity is responsible for hydrolysis of 2-arachidonoylglycerol in rat cerebellar membranes.Biochem Pharmacol. 2004;67:1381–1387.CrossRef
  30. 30.
    Dinh TP, Kathuria S, Piomelli D. RNA interference suggests a primary role for monoacylglycerol lipase in the degradation of the endocannabinoid 2-arachidonoylglycerol.Mol Pharmacol. 2004;66:1260–1264.CrossRef
  31. 31.
    Fezza F, Bisogno T, Minassi A, Appendino G, Mechoulam R, Di Marzo V. Noladin ether, a putative novel endocannabinoid: inactivation mechanisms and a sensitive method for its quantification in rat tissues.FEBS Lett. 2002;513:294–298.CrossRef
  32. 32.
    De Petrocellis L, Davis JB, Di Marzo V. Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors.FEBS Lett. 2001;506:253–256.CrossRef
  33. 33.
    Sheskin T, Hanus L, Slager J, Vogel Z, Mechoulam R. Structural requirements for binding of anandamide-type compounds to the brain cannabinoid receptor.J Med Chem. 1997;40:659–667.CrossRef
  34. 34.
    Fernando SR, Pertwee RG. Evidence that methyl arachidonyl fluorophosphonate is an irreversible cannabinoid receptor antagonist.Br J Pharmacol. 1997;121:1716–1720.CrossRef
  35. 35.
    Savinainen JR, Saario SM, Niemi R, Järvinen T, Laitinen JT. An optimized approach to study endocannabinoid signaling: evidence against constitutive activity of rat brain adenosine A1 and cannabinoid CB1 receptors.Br J Pharmacol. 2003;140:1451–1459.CrossRef
  36. 36.
    Nithipatikom K, Endsley MP, Isbell MA, et al. 2-Arachidonoylglycerol: a novel inhibitor of androgen-independent prostate cancer cell invasion.Cancer Res. 2004;64:8826–8830.CrossRef
  37. 37.
    Kathuria S, Gaetani S, Fegley D, et al. Modulation of anxiety through blockade of anandamide hyyrolysis.Nat Med. 2003;9:76–81.CrossRef
  38. 38.
    Lichtman AH, Leung D, Shelton CC, et al. Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity.J Pharmacol Exp Ther. 2004;311:441–448.CrossRef
  39. 39.
    Huang SM, Bisogno T, Petros TJ, et al. Identification of a new class of molecules, the arachidonyl amino acids, and characterization of one member that inhibits pain.J Biol Chem. 2001;276:42639–42644.CrossRef
  40. 40.
    Bisogno T, Melck D, De Petrocellis L, et al. Arachidonoylserotonin and other novel inhibitors of fatty acid amide hydrolase.Biochem Biophys Res Commun. 1998;248:515–522.CrossRef
  41. 41.
    Ligresti A, Bisogno T, Matias I, et al. Possible endocannabinoid control of colorectal cancer growth.Gastroenterology. 2003;125:677–687.CrossRef
  42. 42.
    Jonsson K-O, Vandevoorde S, Lambert DM, Tiger G, Fowler CJ. Effects of homologues and analogues of palmitoylethanolamide upon the inactivation of the endocannabinoid anandamide.Br J Pharmacol. 2001;133:1263–1275.CrossRef
  43. 43.
    Khanolkar AD, Abadji V, Lin S, et al. Head group analogs of arachidonylethanolamide, the endogenous cannabinoid ligand.J Med Chem. 1996;39:4515–4519.CrossRef
  44. 44.
    Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D. Functional role of high-affinity anandamide transport, as revealed by selective inhibition.Science. 1997;277:1094–1097.CrossRef
  45. 45.
    Jarrahian A, Manna S, Edgemond WS, Campbell WB, Hillard CJ. Structure-activity relationships amongN-arachidonylethanolamine (anandamide) head group analogues for the anandamide transporter.J Neurochem. 2000;74:2597–2606.CrossRef
  46. 46.
    Zygmunt PM, Chuang H, Movahed P, Julius D, Högestätt ED. The anandamide transport inhibitor AM404 activates vanilloid receptors.Eur J Pharmacol. 2000;396:39–42.CrossRef
  47. 47.
    De Petrocellis L, Bisogno T, Davis JB, Pertwee RG, Di Marzo V. Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin-like activity.FEBS Lett. 2000;483:52–56.CrossRef
  48. 48.
    Fowler CJ, Tiger G, Ligresti A, López-Rodríguez ML, Di Marzo V. Selective inhibition of anandamide cellular uptake versus enzymatic hydrolysis—a difficult issue to handle.Eur J Pharmacol. 2004;492:1–11.CrossRef
  49. 49.
    Ortar G, Ligresti A, De Petrocellis L, Morera E, Di Marzo V. Novel selective and metabolically stable inhibitors of anandamide cellular uptake.Biochem Pharmacol. 2003;65:1473–1481.CrossRef
  50. 50.
    López-Rodríguez ML, Viso A, Ortega-Gutiérrez S, et al. Design, synthesis and biological evaluation of new endocannabinoid transporter inhibitors.Eur J Med Chem. 2003;38:403–412.CrossRef
  51. 51.
    Ruiz-Llorente L, Ortega-Gutiérrez S, Viso A, et al. Characterization of an anandamide degradation system in prostate epithelial PC-3 cells: synthesis of new transporter inhibitors as tools for this study.Br J Pharmacol. 2004;141:457–467.CrossRef
  52. 52.
    Benito C, Núñez E, Tolón RM, et al. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains.J Neurosci. 2003;23:11136–11141.
  53. 53.
    Ramírez BG, Blázquez C, Gómez del Pulgar T, Guzmán N, de Ceballos ML. Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation.J Neurosci. 2005;25:1904–1913.CrossRef
  54. 54.
    Giuffrida A, Leweke FM, Gerth CW, et al. Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms.Neuropsychopharmacology. 2004;29:2108–2114.CrossRef
  55. 55.
    Leweke FM, Giuffrida A, Wurster U, Emrich HM, Piomelli D. Elevated endogenous cannabinoids in schizophrenia.Neuroreport. 1999;10:1665–1669.CrossRef
  56. 56.
    Dean B, Sundram S, Bradbury R, Scarr E, Copolov D. Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use.Neuroscience. 2001;103:9–15.CrossRef
  57. 57.
    Zavitsanou K, Garrick T, Huang XF. Selective antagonist [3H]SR141716A binding to cannabinoid CB1 receptors is increased in the anterior cingulate cortex in schizophrenia.Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:355–360.CrossRef
  58. 58.
    De Marchi N, De Petrocellis L, Orlando P, Daniele F, Fezza F, Di Marzo V. Endocannabinoid signalling in the blood of patients with schizophrenia.Lipids Health Dis. 2003;2:1–9.CrossRef
  59. 59.
    Hungund BL, Vinod KY, Kassir SA, et al. Upregulation of CB1 receptors and agonist-stimulated [35S]GTPγS binding in the prefrontal cortex of depressed suicide victims.Mol Psychiatry. 2004;9:184–190.CrossRef
  60. 60.
    Vinod KY, Arango V, Xie S, et al. Elevated levels of endocannabinoids and CB1 receptor-mediated G-protein signaling in the prefrontal cortex of alcoholic suicide victims.Biol Psychiatry. 2005;57:480–486.CrossRef
  61. 61.
    Lastres-Becker I, Cebeira M, de Ceballos ML, et al. Increased cannabinoid CB1 receptor binding and activation of GTP-binding proteins in the basal ganglia of patients with Parkinson’s syndrome and of MPTP-treated marmosets.Eur J Neurosci. 2001;14:1827–1832.CrossRef
  62. 62.
    Glass M, Faull R, Dragunow M. Loss of cannabinoid receptors in the substantia-nigra in Huntington’s disease.Neurosci. 1993;56:523–527.CrossRef
  63. 63.
    Richfield EK, Herkenham M. Selective vulnerability in Huntington’s disease: preferential loss of cannabinoid receptors in lateral globus pallidus.Ann Neurol. 1994;36:577–584.CrossRef
  64. 64.
    Schäbitz W-R, Giuffrida A, Berger C, et al. Release of fatty acid amides in a patient with hemispheric stroke: a microdialysis study.Stroke. 2002;33:2112–2114.CrossRef
  65. 65.
    Maccarrone M, Valensise H, Bari M, Lazzarin N, Romanini C, Finazzi-Agricò A. Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage.Lancet. 2000;355:1326–1329.CrossRef
  66. 66.
    Maccarrone M, Bisogno T, Valensise H, et al. Low fatty acid amide hydrolase and high anandamide levels are associated with failure to achieve an ongoing pregnancy after IVF and embryo transfer.Mol Hum Reprod. 2002;8:188–195.CrossRef
  67. 67.
    Wang Y, Liu Y, Ito 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. 2001;294:73–82.CrossRef
  68. 68.
    Bátkai S, Járai Z, Wagner JA, et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis.Nat Med. 2001;7:827–832.CrossRef
  69. 69.
    Fernández-Rodriguez CM, Romero J, Petros TJ, et al. Circulating endogenous cannabinoid anandamide and portal, systemic and renal hemodynamics in cirrhosis.Liver Int. 2004;24:477–483.CrossRef
  70. 70.
    Julien B, Grenard P, Teixeira-Clerc F, et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver.Gastroenterology. 2005;128:742–755.CrossRef
  71. 71.
    Steffens S, Veillard NR, Arnaud C, et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice.Nature. 2005;434:782–786.CrossRef
  72. 72.
    Maccarrone M, Attinà M, Cartoni A, Bari M, Finazzi-Agricò A. Gas chromatography-mass spectrometry analysis of endogenous cannabinoids in healthy and tumoral human brain and human cells in culture.J Neurochem. 2001;76:594–601.CrossRef
  73. 73.
    Petersen G, Moesgaard B, Schmid PC, et al. Endocannabinoid metabolism in human glioblastomas and meningiomas compared to human non-tumour brain tissue.J Neurochem. 2005;93:299–309.CrossRef
  74. 74.
    Pagotto U, Marsicano G, Fezza F, et al. Normal human pituitary gland and pituitary adenomas express cannabinoid receptor type 1 and synthesize endogenous cannabinoids: first evidence for a direct role of cannabinoids on hormone modulation at the human pituitary level.J Clin Endocrinol Metab. 2001;86:2687–2696.CrossRef
  75. 75.
    Sarfaraz S, Afaq F, Adhami VM, Mukhtar H. Cannabinoid receptor as a novel target for the treatment of prostate cancer.Cancer Res. 2005;65:1635–1641.CrossRef
  76. 76.
    Motobe T, Hashiguchi T, Uchimura T, et al. Endogenous cannbinoids are candidates for lipid mediators of bone cement implantation syndrome.Shock. 2004;21:8–12.CrossRef
  77. 77.
    Baker D, Pryce G, Croxford JL, et al. Endocannabinoids control spasticity in a multiple sclerosis model.FASEB J. 2001;15:300–302.
  78. 78.
    Berrendero F, Sánchez A, Cabranes A, et al. Changes in cannabinoid CB1 receptors in striatal and cortical regions of rats with experimental allergic encephalomyelitis, an animal model of multiple sclerosis.Synapse. 2001;41:195–202.CrossRef
  79. 79.
    Cheng BC, Xu H, Calbay L, Pertwee RG, Coutts A, Forrester JV. Specific CB2 receptor agonist suppresses the murine model of experimental autoimmune uveitis.Invest Ophthalmol Vis Sci. 2004;45:552.CrossRef
  80. 80.
    Witting A, Weydt P, Hong S, Kliot M, Möller T, Stella N. Endocannabinoids accumulate in spinal cord of SOD1G93A transgenic mice.J Neurochem. 2004;89:1555–1557.CrossRef
  81. 81.
    Benito C, Kim W-K, Chavarria I, et al. A glial endogenous cannabinoid system is upregulated in the brains of macaques with simian immunodeficiency virus-induced encephalitis.J Neurosci. 2005;25:2530–2536.CrossRef
  82. 82.
    Adriani W, Caprioli A, Granstrem O, Carli M, Laviola G. The spontaneously hypertensive-rat as an animal model of ADHD evidence for impulsive and non-impulsive subpopulations.Neurosci Biobehav Rev. 2003;27:639–651.CrossRef
  83. 83.
    Di Marzo V, Hill MP, Bisogno T, Crossman AR, Brotchie JM. Enhanced levels of endogenous cannabinoids in the globus pallidus are associated with a reduction in movement in an animal model of Parkinson’s disease.FASEB J. 2000;14:1432–1438.CrossRef
  84. 84.
    Gubellini P, Picconi B, Bari M, et al. Experimental parkinsonism alters endocannabinoid degradation: implications for striatal glutamatergic transmission.J Neurosci. 2002;22:6900–6907.
  85. 85.
    Maccarrone M, Gubellini P, Bari M, et al. Levodopa treatment reverses endocannabinoid system abnormalities in experimental parkinsonism.J Neurochem. 2003;85:1018–1025.CrossRef
  86. 86.
    Fernandez-Espejo E, Caraballo I, Rodriguez de Fonseca F, et al. Experimental parkinsonism alters anandamide precursor synthesis, and functional deficits are improved by AM404: a modulator of endocannabinoid function.Neuropsychopharmacology. 2004;29:1134–1142.CrossRef
  87. 87.
    Ferrer B, Asbrock N, Kathuria S, Piomelli D, Giuffrida A Effects of levodopa on endocannabinoid levels in rat basal ganglia: implications for the treatment of levodopa-induced dyskinesias.Eur J Neurosci. 2003;18:1607–1614.CrossRef
  88. 88.
    Herkenham M, Lynn AB, de Costa BR, Richfield EK. Neuronal localization of cannabinoid receptors in the basal ganglia of the rat.Brain Res. 1991;547:267–274.CrossRef
  89. 89.
    Romero J, Berrendero F, Pérez-Rosado A, et al. Unilateral 6-hydroxydopamine lesions of nigrostriatal dopaminergic neurons increased CB1 receptor mRNA levels in the caudate-putamen.Life Sci. 2000;66:485–494.CrossRef
  90. 90.
    Mailleux P, Vanderhaeghen J-J. Dopaminergic regulation of cannabinoid receptor mRNA levels in the rat caudate-putamen: an in situ hybridization study.J Neurochem. 1993;61:1705–1712.CrossRef
  91. 91.
    Zeng B-Y, Dass B, Owen A, et al. Chronic L-DOPA treatment increases striatal cannabinoid CB1 receptor mRNA expression in 6-hydroxydopamine-lesioned rats.Neurosci Lett. 1999;276:71–74.CrossRef
  92. 92.
    McCaw EA, Hu H, Gomez GT, Hebb ALO, Kelly MEM, Denovan-Wright EM. Structure, expression and regulation of the cannabinoid receptor gene (CB1) in Huntington’s disease transgenic mice.Eur J Biochem. 2004;271:4909–4920.CrossRef
  93. 93.
    Page KJ, Besret L, Jain M, Monagham EM, Dunnett SB, Everitt BJ. Effects of systemic 3-nitropropionic acid-induced lesions of the dorsal striatum on cannabinoid and μ-opioid receptor binding in the basal ganglia.Exp Brain Res. 2000;130:142–150.CrossRef
  94. 94.
    Lastres-Becker I, Fezza F, Cebeira M, et al. Changes in endocannabinoid transmission in the basal ganglia in a rat model of Huntington’s disease.Neuroreport. 2001;12:2125–2129.CrossRef
  95. 95.
    Lastres-Becker I, Bizat N, Boyer F, Hantraye P, Fernández-Ruiz J, Brouillet E. Potential involvement of cannabinoid receptors in 3-nitropropionic acid toxicityin vivo.Neuroreport. 2004;15:2375–2379.CrossRef
  96. 96.
    Lastres-Becker I, Hansen HH, Berrendero F, et al. Alleviation of motor hyperactivity and neurochemical deficits by endocannabinoid uptake inhibition in a rat model of Huntington’s disease.Synapse. 2002;44:23–35.CrossRef
  97. 97.
    Lastres-Becker I, Berrendero F, Lucas JJ, et al. Loss of mRNA levels, binding and activation of GTP-binding proteins for cannabinoid CB1 receptors in the basal ganglia of a transgenic model of Huntington’s disease.Brain Res. 2002;929:236–242.CrossRef
  98. 98.
    Walker JM, Huang SM, Strangman NM, Tsou K, Sañudo-Peña MC. Pain modulation by release of the endogenous cannabinoid anandamide.Proc Natl Acad Sci USA. 1999;96:12198–12203.CrossRef
  99. 99.
    Lim G, Sung B, Ji R-R, Mao J. Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of Win 55,212-2 on neuropathic pain behaviors in rats.Pain. 2003;105:275–283.CrossRef
  100. 100.
    Zhang J, Hoffert C, Vu HK, Groblewski T, Ahmad S, O’Donnell D. Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models.Eur J Neurosci. 2003;17:2750–2754.CrossRef
  101. 101.
    Dinis P, Charrua A, Avelino A, et al. Anandamide-evoked activation of vanilloid receptor 1 contributes to the development of bladder hyperreflexia and nociceptive transmission to spinal dorsal horn neurons in cystitis.J Neurosci. 2004;24:11253–11263.CrossRef
  102. 102.
    Di Marzo V, Goparaju SK, Wang L, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake.Nature. 2001;410:822–825.CrossRef
  103. 103.
    Bensaid M, Gary-Bobo M, Esclangon A, et al. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells.Mol Pharmacol. 2003;63:908–914.CrossRef
  104. 104.
    Maccarrone M, Fride E, Bisogno T, et al. Up-regulation of the endocannabinoid system in the uterus of leptin knockout (ob/ob) mice and implications for fertility.Mol Hum Reprod. 2005;11:21–28.CrossRef
  105. 105.
    Kirkham TC, Williams CM, Fezza F, Di Marzo V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, ing and satiation: stimulation of eating by 2-arachidonoyl glycerol.Br J Pharmacol. 2002;136:550–557.CrossRef
  106. 106.
    Hill MN, Patel S, Carrier EJ, et al. Downregulation of endocannabinoid signaling in the hippocampus following chronic unpredictable stress.Neuropsychopharmacology. 2005;30:508–515.CrossRef
  107. 107.
    Patel S, Roelke CT, Rademacher DJ, Hillard CJ. Inhibition of restraint stress-induced neural and behavioural activation by endogenous cannabinoid signalling.Eur J Neurosci. 2005;21:1057–1069.CrossRef
  108. 108.
    Marsicano G, Wotjak CT, Azad SC, et al. The endogenous cannabinoid system controls extinction of aversive memories.Nature. 2002;418:530–534.CrossRef
  109. 109.
    Liu P, Bilkey DK, Darlington CL, Smith PF. Cannabinoid CB1 receptor protein expression in the rat hippocampus and entorhinal, perirhinal, postrhinal and temporal cortices: regional variations and agerelated changes.Brain Res. 2003;979:235–239.CrossRef
  110. 110.
    Sparling PB, Giuffrida A, Piomelli D, Rosskopf L, Dietrich A. Exercise activates the endocannabinoid system.Neuroreport. 2003;14:2209–2211.CrossRef
  111. 111.
    Bátkai S, Pacher P, Osei-Hyiaman D, et al. Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension.Circulation. 2004;110:1996–2002.CrossRef
  112. 112.
    Domenicali M, Ros J, Fernández-Varo G, et al. Increased anandamide induced relaxation in mesenteric arteries of cirrhotic rats: role of cannabinoid and vanilloid receptors.Gut. 2005;54:522–527.CrossRef
  113. 113.
    Varga K, Wagner JA, Bridgen DT, Kunos G. Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension.FASEB J. 1998;12:1035–1044.
  114. 114.
    Liu J, Bátkai S, Pacher P, et al. Lipopolysaccharide induces anandamide synthesis in macrophages via CD14/MAPK/phosphoinositide 3-kinase/NF-κB independently of platelet-activating factor.J Biol Chem. 2003;278:45034–45039.CrossRef
  115. 115.
    Maccarrone M, De Petrocellis L, Bari M, et al. Lipopolysaccharide downregulates fatty acid amide hydrolase expression and increases anandamide levels in human peripheral lymphocytes.Arch Biochem Biophys. 2001;393:321–328.CrossRef
  116. 116.
    Wagner JA, Hu K, Bauersachs J, et al. Endogenous cannabinoids mediate hypotension after experimental myocardial infarction.J Am Coll Cardiol. 2001;38:2048–2054.CrossRef
  117. 117.
    Izzo AA, Fezza F, Capasso R, et al. Cannabinoid CB1-receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation.Br J Pharmacol. 2001;134:563–570.CrossRef
  118. 118.
    Massa F, Marsicano G, Hermann H, et al. The endogenous cannabinoid system protects against colonic inflammation.J Clin Invest. 2004;113:1202–1209.
  119. 119.
    Izzo AA, Capasso F, Costagliola A, et al. An endogenous cannabinoid tone attenuates cholera toxin-induced fluid accumulation in mice.Gastroenterology. 2003;125:765–774.CrossRef
  120. 120.
    McVey DC, Schmid PC, Schmid HHO, Vigna SR. Endocannabinoids induce ileitis in rats via the capsaicin receptor (VR1).J Pharmacol Exp Ther. 2003;304:713–722.CrossRef
  121. 121.
    Mascolo N, Izzo AA, Ligresti A, et al. The endocannabinoid system and the molecular basis of paralytic ileus in mice.FASEB J. 2002;16:U131-U51.
  122. 122.
    Jin KL, Mao XO, Goldsmith PC, Greenberg DA. CB1 cannabinoid receptor induction in experimental stroke.Ann Neurol. 2000;48:257–261.CrossRef
  123. 123.
    Muthian S, Rademacher DJ, Roelke CT, Gross GJ, Hillard CJ. Anandamide content is increased and CB1 cannabinoid receptor blockade is protective during transient, focal cerebral ischemia.Neuroscience. 2004;129:743–750.CrossRef
  124. 124.
    Kurabayashi M, Takeyoshi I, Yoshinari D, Matsumoto K, Maruyama I, Morishita Y. 2-Arachidonoylglycerol increases in ischemia-reperfusion injury of the rat liver.J Invest Surg. 2005;18:25–31.CrossRef
  125. 125.
    Hansen HH, Schmid PC, Bittigau P, et al. Anandamide, but not 2-arachidonoylglycerol, accumulates duringin vivo neurodegeneration.J Neurochem. 2001;78:1415–1427.CrossRef
  126. 126.
    Panikashvili D, Simeonidou C, Ben-Shabat S, et al. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury.Nature. 2001;413:527–531.CrossRef
  127. 127.
    Sugiura T, Yoshinaga N, Kondo S, Waku K, Ishima Y. Generation of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, in picrotoxinin-administered rat brain.Biochem Biophys Res Commun. 2000;271:654–658.CrossRef
  128. 128.
    Marsicano G, Goodenough S, Monory K, et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity.Science. 2003;302:84–88.CrossRef
  129. 129.
    Chen K, Ratzliff A, Hilgenberg L, et al. Long-term plasticity of endocannabinoid signaling induced by developmental febrile seizures.Neuron. 2003;39:599–611.CrossRef
  130. 130.
    Maccarrone M, Piccirilli S, Battista N, et al. Enhanced anandamide degradation is associated with neuronal apoptosis induced by the HIV-1 coat glycoprotein gp120 in the rat neocortex.J Neurochem. 2004;89:1293–1300.CrossRef
  131. 131.
    Sánchez C, de Ceballos ML, Gómez del Pulgar T, et al. Inhibition of glioma growth in vivo by selective activation of the CB2 cannabinoid receptor.Cancer Res. 2001;61:5784–5789.
  132. 132.
    Burstein SH, Rossetti RG, Yagen B, Zurier RB. Oxidative metabolism of anandamide.Prostaglandins Other Lipid Mediat. 2000;61:29–41.CrossRef
  133. 133.
    de Lago E, Ligresti A, Ortar G, et al. In vivo pharmacological actions of 2 novel inhibitors of anandamide cellular uptake.Eur J Pharmacol. 2004;484:249–257.CrossRef
  134. 134.
    Burstein SH, Huang SM, Petros TJ, Rossetti RG, Walker JM, Zurier RB. Regulation of anandamide tissue levels byN-arachidonylglycine.Biochem Pharmacol. 2002;64:1147–1150.CrossRef
  135. 135.
    Cravatt BF, Demarest K, Patricelli MP, et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase.Proc Natl Acad Sci USA. 2001;98:9371–9376.CrossRef
  136. 136.
    Lichtman AH, Shelton CC, Advani T, Cravatt BF. Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia.Pain. 2004;109:319–327.CrossRef
  137. 137.
    Cravatt BF, Saghatelian A, Hawkins EG, Clement AB, Bracey MH, Lichtman AH. Functional disassociation of the central and peripheral fatty acid amide signaling systems.Proc Natl Acad Sci USA. 2004;101:10821–10826.CrossRef
  138. 138.
    Martin BR, Lichtman AH. Cannabinoid transmission and pain perception.Neurobiol Dis. 1998;5:447–461.CrossRef
  139. 139.
    Pertwee RG. Cannabinoid receptors and pain.Prog Neurobiol. 2001;63:569–611.CrossRef
  140. 140.
    Walker JM, Hohman AG. Cannabinoid mechanisms of pain suppression. In: Pertwee RG, ed.Cannabinoids, Handbook of Experimental Pharmacolology. Heidelberg, Germany: Springer-Verlag; 2005;168:509–54.
  141. 141.
    Herzberg U, Eliav E, Bennett GJ, Kopin IJ. The analgesic effects ofR(+)-WIN 55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain.Neurosci Lett. 1997;221:157–160.CrossRef
  142. 142.
    Edsall SA, Knapp RJ, Vanderah TW, Roeske WR, Consroe P, Yamamura HI. Antisense oligodeoxynucleotide treatment to the brain cannabinoid receptor inhibits antinociception.Neuroreport. 1996;7:593–596.CrossRef
  143. 143.
    Richardson JD, Aanonsen L, Hargreaves KM. Hypoactivity of the spinal cannabinoid system results in NMDA-dependent hyperalgesia.J Neurosci. 1998;18:451–457.
  144. 144.
    Dogrul A, Gardell LR, Ma S, Ossipov MH, Porreca F, Lai J. ‘Knock-down’ of spinal CB1 receptors produces abnormal pain and elevates spinal dynorphin content in mice.Pain. 2002;100:203–209.CrossRef
  145. 145.
    Valverde O, Ledent C, Beslot F, Parmentier M, Roques BP. Reduction of stress-induced analgesia but not of exogenous opioid effects in mice lacking CB1 receptors.Eur J Neurosci. 2000;12:533–539.CrossRef
  146. 146.
    Ibrahim MM, Deng H, Zvonok A, et al. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS.Proc Natl Acad Sci USA. 2003;100:10529–10533.CrossRef
  147. 147.
    Ledent C, Valverde O, Cossu G, et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice.Science. 1999;283:401–404.CrossRef
  148. 148.
    Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI. Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice.Proc Natl Acad Sci USA. 1999;96:5780–5785.CrossRef
  149. 149.
    Hanus L, Breuer A, Tchilibon S, et al. HU-308: a specific agonist for CB2, a peripheral cannabinoid receptor.Proc Natl Acad Sci USA. 1999;96:14228–14233.CrossRef
  150. 150.
    Clayton N, Marshall FH, Bountra C, O’Shaughnessy CT. CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain.Pain. 2002;96:253–260.CrossRef
  151. 151.
    Valenzano KJ, Tafesse L, Lee G, et al. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW 405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy.Neuropharmacology. 2005;48:658–672.CrossRef
  152. 152.
    Malan TP, Ibrahim MM, Deng H, et al. CB2 cannabinoid receptor-mediated peripheral antinociception.Pain. 2001;93:239–245.CrossRef
  153. 153.
    Nackley AG, Makriyannis A, Hohmann AG. Selective activation of cannabinoid CB2 receptors suppresses spinal Fos protein expression and pain behavior in a rat model of inflammation.Neuroscience. 2003;119:747–757.CrossRef
  154. 154.
    Quartilho A, Mata HP, Ibrahim MM, et al. Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors.Anesthesiology. 2003;99:955–960.CrossRef
  155. 155.
    Hohmann AG, Farthing JN, Zvonok AM, Makriyannis A. Selective activation of cannabinoid CB2 receptors suppresses hyperalgesia evoked by intradermal capsaicin.J Pharmacol Exp Ther. 2004;308:446–453.CrossRef
  156. 156.
    Ibrahim MM, Porreca F, Lai J, et al. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids.Proc Natl Acad Sci USA. 2005;102:3093–3098.CrossRef
  157. 157.
    Ross RA, Coutts AA, McFarlane SM, et al. Actions of cannabinoid receptor ligands on rat cultured sensory neurones: implications for antinociception.Neuropharmacology. 2001;40:221–232.CrossRef
  158. 158.
    Holt S, Comelli F, Costa B, Fowler CJ. Inhibitors of fatty acid amide hydrolase reduce carrageenan induced hind paw inflammation in pentobarbital-treated mice: comparison with indomethacin and possible involvement of cannabinoid receptors.Br J Pharmacol. 2005;146:467–476.CrossRef
  159. 159.
    Calignano A, La Rana G, Giuffrida A, Piomelli D. Control of pain initiation by endogenous cannabinoids.Nature. 1998;394:277–281.CrossRef
  160. 160.
    Beaulieu P, Bisogno T, Punwar S, et al. Role of the endogenous cannabinoid system in the formalin test of persistent pain in the rat.Eur J Pharmacol. 2000;396:85–92.CrossRef
  161. 161.
    Notcutt W, Price M, Miller R, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘N of 1’ studies.Anaesthesia. 2004;59:440–452.CrossRef
  162. 162.
    Noyes R, Brunk SF, Baram DA, Canter A. Analgesic effect of delta-9-tetrahydrocannabinol.J Clin Pharmacol. 1975;15:139–143.
  163. 163.
    Noyes R, Brunk SF, Avery DH, Canter A. Analgesic properties of delta-9-tetrahydrocannabinol and codeine.Clin Pharmacol Ther. 1975;18:84–89.
  164. 164.
    Pertwee RG. Cannabinoids and multiple sclerosisPharmacol Ther. 2002;95:165–174.CrossRef
  165. 165.
    Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms.Clin Rehabil. 2003;17:21–29.CrossRef
  166. 166.
    Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial.Lancet. 2003;362:1517–1526.CrossRef
  167. 167.
    Gauter B, Rukwied R, Konrad C. Cannabinoid agonists in the treatment of blepharospasm—a case report study.Neuroendocrinol Lett. 2004;25:45–48.
  168. 168.
    Brady CM, DasGupta R, Dalton C, Wiseman OJ, Berkley KJ, Fowler CJ. An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis.Mult Scler. 2004;10:425–433.CrossRef
  169. 169.
    Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomized double blind placebo controlled crossover trial.BMJ. 2004;329:253–257.CrossRef
  170. 170.
    Iwamura H, Suzuki H, Ueda Y, Kaya T, Inaba T. In vitro and in vivo pharmacological characterization of JTE-907, a novel selective ligand for cannabinoid CB2 receptor.J Pharmacol Exp Ther. 2001;296:420–425.
  171. 171.
    Lavey BJ, Kozlowski JA, Hipkin RW, et al. Triaryl bis-sulfones as a new class of cannabinoid CB2 receptor inhibitors: identification of a lead and initial SAR studies.Bioorg Med Chem Lett. 2005;15:783–786.CrossRef
  172. 172.
    Lunn CA. Immune modulation by cannabinoids: targetting the cannabinoid CB2 receptor. Symposium on cannabinoid receptors: pharmacological opportunities for obesity and inflammation: New York Academy of Sciences, 2004. Available at: http://www.nyas.org/ebriefreps/main.asp?intSubsectionID-1406 (Accessed).
  173. 173.
    Costa B, Colleoni M, Trovato AE, Comelli F, Franke C, Giognoni G. Anandamide transport and hydrolysis as targets for the treatment of neuropathic pain: Effects of AM404 and URB597 in rats with chronic constriction injury of the sciatic nerve. 2005 Symposium on the Cannabinoids; June 24–27; Clearwater Beach, FL. Burlington, VT: International Cannabinoid Research Society; 2005:33.
  174. 174.
    Mestre L, Correa F, Arévalo-Martin A, et al. Pharmacological modulation of the endocannabinoid system in a viral model of multiple sclerosis.J Neurochem. 2005;92:1327–1339.CrossRef
  175. 175.
    Pryce G, Ahmed Z, Hankey DJR, et al. Cannabinoids inhibit neurodegeneration in models of multiple sclerosis.Brain. 2003;126:2191–2202.CrossRef
  176. 176.
    Baker D, Pryce G, Croxford JL, et al. Cannabinoids control spasticity and tremor in a multiple sclerosis model.Nature. 2000;404:84–87.CrossRef
  177. 177.
    Brooks JW, Pryce G, Bisogno T, et al. Arvanil-induced inhibition of spasticity and persistent pain: evidence for therapeutic sites of action different from the vanilloid VR1 receptor and cannabinoid CB1/CB2 receptors.Eur J Pharmacol. 2002;439:83–92.CrossRef
  178. 178.
    Wilkinson JD, Whalley BJ, Baker D, et al. Medicinal cannabis: is {ieE653-1} necessary for all its effects?.J Pharm Pharmacol. 2003;55:1687–1694.CrossRef
  179. 179.
    Lyman WD, Sonett JR, Brosnan CF, Elkin R, Bornstein MB. {ieE653-2} a novel treatment for experimental autoimmune encephalomyelitis.J Neuroimmunol. 1989;23:73–81.CrossRef
  180. 180.
    Wirguin I, Mechoulam R, Breuer A, Schezen E, Weidenfeld J, Brenner T. Suppression of experimental autoimmune encephalomyelitis by cannabinoids.Immunopharmacology. 1994;28:209–214.CrossRef
  181. 181.
    Croxford JL, Miller SD. Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoidR(+)WIN55,212.J Clin Invest. 2003;111:1231–1240.
  182. 182.
    Arévalo-Martin N, Vela JM, Molina-Holgado E, Borrell J, Guaza C. Therapeutic action of cannabinoids in a murine model of multiple sclerosis.J Neurosci. 2003;23:2511–2516.
  183. 183.
    Vaney C, Heinzel-Gutenbrunner M, Jobin P, 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. 2004;10:417–424.CrossRef
  184. 184.
    Wade DT, 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. 2004;10:434–441.CrossRef
  185. 185.
    Killestein J, Hoogervorst ELJ, Reif M, et al. Safety, tolerability, and efficacy of orally administered cannabinoids in MS.Neurology. 2002;58:1404–1407.
  186. 186.
    Bifulco M, Laezza C, Valenti M, Ligresti A, Portella G, Di Marzo V. A new strategy to block tumor growth by inhibiting endocannabinoid inactivation.FASEB J. 2004;18:U320-U33.
  187. 187.
    Bifulco M, Laezza C, Portella G, et al. Control by the endogenous cannabinoid system ofras oncogene-dependent tumor growth.FASEB J. 2001;15:U100-U16.
  188. 188.
    Bifulco M, Di Marzo V. Targeting the endocannabinoid system in cancer therapy: a call for further research.Nat Med. 2002;8:547–550.CrossRef
  189. 189.
    Portella G, Laezza C, Laccetti P, De Petrocellis L, Di Marzo V, Bifulco M. Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis.FASEB J. 2003;17:U458-U74.
  190. 190.
    Guzmán M. Cannabinoids: potential anticancer agents.Nat Rev Cancer. 2003;3:745–755.CrossRef
  191. 191.
    Guzmán M. Effects on cell viability In: Pertwee RG, ed.Cannabinoids Handbook of Experimental Pharmacolology. Heidelberg, Germany: Springer-Verlag; 2005;168:627–642.
  192. 192.
    Izzo AA, Coutts AA. Cannabinoids and the digestive tract. In: Pertwee RG, ed.Cannabinoids, Handbook of Experimental Pharmacolology. Heidelberg, Germany: Springer-Verlag; 2005;168:573–598.
  193. 193.
    Panikashvili D, Mechoulam R, Beni SM, Alexandrovich A, Shohami E. CB1 cannabinoid receptors are involved in neuroprotection via NF-κB inhibition.J Cereb Blood Flow Metab. 2005;25:477–484.CrossRef
  194. 194.
    El Banoua F, Caraballo I, Flores JA, Galan-Rodriguez B, Fernandez-Espejo E. Effects on turning of microinjections into basal ganglia of D1 and D2 dopamine receptors agonists and the cannabinoid CB1 antagonist SR 141716A in a rat Parkinson’s model.Neurobiol Dis. 2004;16:377–385.CrossRef
  195. 195.
    Fernandez-Espejo E, Caraballo I, Rodriguez de Fonseca F, et al. Cannabinoid CB1 antagonists possess antiparkinsonian efficacy only in rats with very severe nigral lesion in experimental parkinsonism.Neurobiol Dis. 2005;18:591–601.CrossRef
  196. 196.
    Meschler JP, Howlett AC, Madras BK. Cannabinoid receptor agonist and antagonist effects on motor function in normal and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-treated non-human primates.Psychopharmacology (Berl). 2001;156:79–85.CrossRef
  197. 197.
    Wagner JA, Varga K, Ellis EF, Rzigalinski BA, Martin BR, Kunos G. Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock.Nature. 1997;390:518–521.CrossRef
  198. 198.
    Kadoi Y, Hinohara H, Kunimoto F, Kuwano H, Saito S, Goto F. Effects of AM281, a cannabinoid antagonist, on systemic haemodynamics, internal carotid artery blood flow and mortality in septic shock in rats.Br J Anaesth. 2005;94:563–568.CrossRef
  199. 199.
    Robson PJ. Human studies of cannabinoids and medicinal cannabis. In: Pertwee RG, ed.Cannabinoids, Handbook Exp Pharmacol. Heidelberg, Germany: Springer-Verlag; 2005:719–756.
  200. 200.
    Robson PJ, Guy GW. Clinical studies of cannabis-based medicines. In: Guy GW, Whittle BA, Robson PJ, eds.The Medicinal Uses of Cannabis and Cannabinoids. London, UK: Pharmaceutical Press; 2005:229–269.
  201. 201.
    Consroe P, Musty R, Rein J, Tillery W, Pertwee R. The perceived effects of smoked cannabis on patients with multiple sclerosis.Eur Neurol 1997;38:44–48.CrossRef
  202. 202.
    Ware MA, Adams H, Guy GW. The medicinal use of cannabis in the UK: results of a nationwide survey.Int J Clin Pract. 2005;59:291–295.CrossRef
  203. 203.
    De Vry J, Denzer D, Reissmueller E, et al. 3-[2-cyano-3-(trifluoro methyl)phenoxy]phenyl-4,4,4-trifluoro-1-butanesulfonate (BAY 59-3074): a novel cannabinoid CB1/CB2 receptor partial agonist with antihyperalgesic and antiallodynic effects.J Pharmacol Exp Ther. 2004;310:620–632.CrossRef
  204. 204.
    Rukwied R, Watkinson A, McGlone F, Dvorak M. Cannabinoid agonists attenuate capsaicin-induced responses in human skin.Pain. 2003;102:283–288.CrossRef
  205. 205.
    Dvorak M, Watkinson A, McGlone F, Rukwied R. Histamine-induced responses are attenuated by a cannabinoid receptor agonist in human skin.Inflamm Res. 2003;52:238–245.
  206. 206.
    Cichewicz DL. Synergistic interactions between cannabinoid and opioid analgesics.Life Sci. 2004;74:1317–1324.CrossRef
  207. 207.
    Holdcroft A, Smith M, Jacklin A, et al. Pain relief with oral cannabinoids in familial Mediterranean fever.Anaesthesia. 1997;52:483–488.CrossRef
  208. 208.
    Pertwee RG. The pharmacology and therapeutic potential of cannabidiol. In: Di Marzo V, ed.Cannabinoids. New York, NY: Kluwer Academic/Plenum Publishers; 2004:32–83.
  209. 209.
    Mendelson WB, Basile AS. The hypnotic actions of the fatty acid amide, oleamide.Neuropsychopharmacology. 2001;25:S36-S39.CrossRef
  210. 210.
    Pertwee RG, Ross RA. Cannabinoid receptors and their ligands.Prostaglandins Leukot Essent Fatty Acids. 2002;66:101–121.CrossRef
  211. 211.
    Sim-Selley LJ. Regulation of cannabinoid CB1 receptors in the central nervous system by chronic cannabinoids.Crit Rev Neurobiol. 2003;15:91–119.CrossRef
  212. 212.
    Lichtman AH, Martin BR. Cannabinoid tolerance and dependence. In: Pertwee RG, ed.Cannabinoids, Handbook of Experimental Pharmacolology. Heidelberg, Germany: Springer-Verlag; 2005;168:691–717.
  213. 213.
    De Vry J, Jentzsch KR, Kuhl E, Eckel G. Behavioral effects of cannabinoids show differential sensitivity to cannabinoid receptor blockade and tolerance development.Behav Pharmacol. 2004;15:1–12.CrossRef
  214. 214.
    Paria BC, Dey SK. Ligand-receptor signaling with endocannabinoids in preimplantation embryo development and implantation.Chem Phys Lipids. 2000;108:211–220.CrossRef
  215. 215.
    Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study.Lancet. 2005;365:1389–1397.CrossRef
  216. 216.
    Idris AI, van’t Hof RJ, Greig IR, Ridge SA, Baker D, Ross RA, Ralston SH. Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors.Nat Med. 2005;11:774–779.CrossRef
  217. 217.
    Brown AJ, Ueno S, Suen K, Dowell SJ, Wise A Molecular identification of GPR55 as a third G protein-coupled receptor responsive to cannabinoid ligands. Symposium on the Cannabinoids; June 24–27; Clearwater Beach, FL. Burlington, VT: International Cannabinoid Research Society; 2005, 16.
  218. 218.
    Sjögren S, Ryberg E, Lindblom A, et al. A new receptor for cannabinoid ligands Symposium on the Cannabinoids; June 24–27; Clearwater Beach, FL. Burlington, VT: International Cannabinoid Research Society; 2005, 106.
  219. 219.
    Hohmann AG, Suplita RL, Bolton NM, et al. An endocannabinoid mechanism for stress-induced analgesia.Nature. 2005;435:1108–1112.CrossRef

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© American Association of Pharmaceutical Scientists 2005

Authors and Affiliations

  1. 1.School of Medical Sciences, Institute of Medical SciencesUniversity of AberdeenAberdeenScotland, UK

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