Skip to main content
PMC home page
The AAPS Journal logoLink to The AAPS Journal
. 2005 Oct 24;7(3):E625–E654. doi: 10.1208/aapsj070364

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

Roger G Pertwee 1,✉
PMCID: PMC2751266  PMID: 16353941

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

Full Text

The Full Text of this article is available as a PDF (341.6 KB).

References

  • 1.Howlett AC, Barth F, Bonner TI, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54:161–202. doi: 10.1124/pr.54.2.161. [DOI] [PubMed] [Google Scholar]
  • 2.Pertwee RG. Pharmacological actions of cannabinoids. In: Pertwee RG, editor. Cannabinoids, Handbook of Experimental Pharmacology. Heidelberg, Germany: Springer-Verlag; 2005. pp. 1–51. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/346561a0. [DOI] [PubMed] [Google Scholar]
  • 4.Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61–65. doi: 10.1038/365061a0. [DOI] [PubMed] [Google Scholar]
  • 5.Pertwee RG. Pharmacology of cannabinoid receptor ligands. Curr Med Chem. 1999;6:635–664. [PubMed] [Google Scholar]
  • 6.Pertwee RG. Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci. 2005;76:1307–1324. doi: 10.1016/j.lfs.2004.10.025. [DOI] [PubMed] [Google Scholar]
  • 7.Pertwee RG. Novel pharmacological targets for cannabinoids. Curr Neuropharmacol. 2004;2:9–29. doi: 10.2174/1570159043476927. [DOI] [Google Scholar]
  • 8.Price MRBaillie GThomas A. Allosteric modulation of the cannabinoid CB1 receptor.Mol Pharmacol. In press. [DOI] [PubMed]
  • 9.Bradshaw HB, Walker JM. The expanding field of cannabimimetic and related lipid mediators. Br J Pharmacol. 2005;144:459–465. doi: 10.1038/sj.bjp.0706093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.bcp.2004.08.033. [DOI] [PubMed] [Google Scholar]
  • 11.Cabral GA, Staab A. Effects on the immune system. In: Pertwee RG, editor. Cannabinoids, Handbook of Experimental Pharmacology. Heidelberg, Germany: Springer-Verlag; 2005. pp. 385–423. [DOI] [PubMed] [Google Scholar]
  • 12.Szabo B, Schlicker E. Effects of cannabinoids on neurotransmission. In: Pertwee RG, editor. Cannabinoids, Handbook of Experimental Pharmacology. Heidelberg, Germany: Springer-Verlag; 2005. pp. 327–365. [DOI] [PubMed] [Google Scholar]
  • 13.Vaughan CW, Christie MJ. Retrograde signalling by endocannabinoids. In: Pertwee RG, editor. Cannabinoids, Handbook of Experimental Pharmacology. Heidelberg, Germany: Springer-Verlag; 2005. pp. 367–383. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/sj.bjp.0705711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/sj.bjp.0705902. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Di Marzo V, De Petrocellis L, Bisogno T. The biosynthesis, fate and pharmacological properties of endocannabinoids. In: Pertwee RG, editor. Camabinoids, Handbook of Experimental Pharmacology. Heidelberg, Germany: Springer-Verlag; 2005. pp. 147–185. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1042/0264-6021:3510817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/sj.bjp.0705607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1124/jpet.301.3.1020. [DOI] [PubMed] [Google Scholar]
  • 20.Cravatt BF, Lichtman AH. The endogenous cannabinoid system and its role in nociceptive behavior. J Neurobiol. 2004;61:149–160. doi: 10.1002/neu.20080. [DOI] [PubMed] [Google Scholar]
  • 21.Hillard CJ, Jarrahian A. Cellular accumulation of anandamide: consensus and controversy. Br J Pharmacol. 2003;140:802–808. doi: 10.1038/sj.bjp.0705468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Ueda N. Endocannabinoid hydrolases. Prostaglandins Other Lipid Mediat. 2002;68–9:521–534. doi: 10.1016/S0090-6980(02)00053-9. [DOI] [PubMed] [Google Scholar]
  • 23.Ho W-SV, Hillard CJ. Modulators of endocannabinoid enzymic hydrolysis and membrane transport. In: Pertwee RG, editor. Cannabinoids, Handbook of Experimental Pharmacology. Heidelberg, Germany: Springer-Verlag; 2005. pp. 187–207. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1111/j.1460-9568.2004.03428.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1074/jbc.M106261200. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1007/s00018-004-4494-0. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1124/jpet.104.078980. [DOI] [PubMed] [Google Scholar]
  • 28.Kozak KR, Marnett LJ. Oxidative metabolism of endocannabinoids. Prostaglandins Leukot Essent Fatty Acids. 2002;66:211–220. doi: 10.1054/plef.2001.0359. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.bcp.2003.12.003. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1124/mol.104.002071. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0014-5793(02)02341-4. [DOI] [PubMed] [Google Scholar]
  • 32.De Petrocellis L, Davis JB, Di Marzo V. Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors. FEBS Lett. 2001;506:253–256. doi: 10.1016/S0014-5793(01)02934-9. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1021/jm960752x. [DOI] [PubMed] [Google Scholar]
  • 34.Fernando SR, Pertwee RG. Evidence that methyl arachidonyl fluorophosphonate is an irreversible cannabinoid receptor antagonist. Br J Pharmacol. 1997;121:1716–1720. doi: 10.1038/sj.bjp.0701303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/sj.bjp.0705577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1158/0008-5472.CAN-04-3136. [DOI] [PubMed] [Google Scholar]
  • 37.Kathuria S, Gaetani S, Fegley D, et al. Modulation of anxiety through blockade of anandamide hyyrolysis. Nat Med. 2003;9:76–81. doi: 10.1038/nm803. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1124/jpet.104.069401. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1074/jbc.M107351200. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1006/bbrc.1998.8874. [DOI] [PubMed] [Google Scholar]
  • 41.Ligresti A, Bisogno T, Matias I, et al. Possible endocannabinoid control of colorectal cancer growth. Gastroenterology. 2003;125:677–687. doi: 10.1016/S0016-5085(03)00881-3. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/sj.bjp.0704199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1021/jm960152y. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1126/science.277.5329.1094. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1046/j.1471-4159.2000.0742597.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0014-2999(00)00207-7. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0014-5793(00)02082-2. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.ejphar.2004.03.048. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0006-2952(03)00109-6. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0223-5234(03)00045-X. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/sj.bjp.0705628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1523/JNEUROSCI.23-35-11136.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1523/JNEUROSCI.4540-04.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/sj.npp.1300558. [DOI] [PubMed] [Google Scholar]
  • 55.Leweke FM, Giuffrida A, Wurster U, Emrich HM, Piomelli D. Elevated endogenous cannabinoids in schizophrenia. Neuroreport. 1999;10:1665–1669. doi: 10.1097/00001756-199906030-00008. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0306-4522(00)00552-2. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.pnpbp.2003.11.005. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1186/1476-511X-2-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/sj.mp.4001376. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.biopsych.2004.11.033. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1046/j.0953-816x.2001.01812.x. [DOI] [PubMed] [Google Scholar]
  • 62.Glass M, Faull R, Dragunow M. Loss of cannabinoid receptors in the substantia-nigra in Huntington’s disease. Neurosci. 1993;56:523–527. doi: 10.1016/0306-4522(93)90352-G. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1002/ana.410360406. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1161/01.STR.0000023491.63693.18. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0140-6736(00)02115-2. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1093/molehr/8.2.188. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1006/abio.2001.5015. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/89953. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1111/j.1478-3231.2004.0945.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1053/j.gastro.2004.12.050. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/nature03389. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1046/j.1471-4159.2001.00092.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1111/j.1471-4159.2005.03013.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1210/jc.86.6.2687. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1158/0008-5472.CAN-04-3410. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1097/01.SHK.0000094766.36694.49. [DOI] [PubMed] [Google Scholar]
  • 77.Baker D, Pryce G, Croxford JL, et al. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J. 2001;15:300–302. doi: 10.1096/fj.00-0399fje. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1002/syn.1075. [DOI] [PubMed] [Google Scholar]
  • 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;45:552–552. doi: 10.1167/iovs.03-0749. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1111/j.1471-4159.2004.02544.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1523/JNEUROSCI.3923-04.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.neubiorev.2003.08.007. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1096/fj.14.10.1432. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1523/JNEUROSCI.22-16-06900.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Maccarrone M, Gubellini P, Bari M, et al. Levodopa treatment reverses endocannabinoid system abnormalities in experimental parkinsonism. J Neurochem. 2003;85:1018–1025. doi: 10.1046/j.1471-4159.2003.01759.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/sj.npp.1300407. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1046/j.1460-9568.2003.02896.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/0006-8993(91)90970-7. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0024-3205(99)00618-9. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1111/j.1471-4159.1993.tb09807.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0304-3940(99)00762-4. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1111/j.1432-1033.2004.04460.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1007/s002210050016. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1097/00001756-200107200-00017. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1097/00001756-200410250-00015. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1002/syn.10054. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0006-8993(01)03403-5. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1073/pnas.96.21.12198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0304-3959(03)00242-2. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1046/j.1460-9568.2003.02704.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1523/JNEUROSCI.2657-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Di Marzo V, Goparaju SK, Wang L, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature. 2001;410:822–825. doi: 10.1038/35071088. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1124/mol.63.4.908. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1093/molehr/gah130. [DOI] [PubMed] [Google Scholar]
  • 105.Kirkham TC, Williams CM, Fezza F, Di Marzo V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol. 2002;136:550–557. doi: 10.1038/sj.bjp.0704767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/sj.npp.1300601. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1111/j.1460-9568.2005.03916.x. [DOI] [PubMed] [Google Scholar]
  • 108.Marsicano G, Wotjak CT, Azad SC, et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature. 2002;418:530–534. doi: 10.1038/nature00839. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0006-8993(03)02872-5. [DOI] [PubMed] [Google Scholar]
  • 110.Sparling PB, Giuffrida A, Piomelli D, Rosskopf L, Dietrich A. Exercise activates the endocannabinoid system. Neuroreport. 2003;14:2209–2211. doi: 10.1097/00001756-200312020-00015. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1161/01.CIR.0000143230.23252.D2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1136/gut.2004.051599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1096/fasebj.12.11.1035. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1074/jbc.M306062200. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1006/abbi.2001.2500. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0735-1097(01)01671-0. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/sj.bjp.0704293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 118.Massa F, Marsicano G, Hermann H, et al. The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest. 2004;113:1202–1209. doi: 10.1172/JCI19465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0016-5085(03)00892-8. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1124/jpet.102.043893. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1096/fj.02-0338fje. [DOI] [PubMed] [Google Scholar]
  • 122.Jin KL, Mao XO, Goldsmith PC, Greenberg DA. CB1 cannabinoid receptor induction in experimental stroke. Ann Neurol. 2000;48:257–261. doi: 10.1002/1531-8249(200008)48:2<257::AID-ANA18>3.0.CO;2-P. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.neuroscience.2004.08.044. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1080/08941930590905189. [DOI] [PubMed] [Google Scholar]
  • 125.Hansen HH, Schmid PC, Bittigau P, et al. Anandamide, but not 2-arachidonoylglycerol, accumulates duringin vivo neurodegeneration. J Neurochem. 2001;78:1415–1427. doi: 10.1046/j.1471-4159.2001.00542.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/35097089. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1006/bbrc.2000.2686. [DOI] [PubMed] [Google Scholar]
  • 128.Marsicano G, Goodenough S, Monory K, et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science. 2003;302:84–88. doi: 10.1126/science.1088208. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0896-6273(03)00499-9. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1111/j.1471-4159.2004.02430.x. [DOI] [PubMed] [Google Scholar]
  • 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. [PubMed] [Google Scholar]
  • 132.Burstein SH, Rossetti RG, Yagen B, Zurier RB. Oxidative metabolism of anandamide. Prostaglandins Other Lipid Mediat. 2000;61:29–41. doi: 10.1016/S0090-6980(00)00053-8. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.ejphar.2003.11.027. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0006-2952(02)01301-1. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1073/pnas.161191698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.pain.2004.01.022. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1073/pnas.0401292101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 138.Martin BR, Lichtman AH. Cannabinoid transmission and pain perception. Neurobiol Dis. 1998;5:447–461. doi: 10.1006/nbdi.1998.0218. [DOI] [PubMed] [Google Scholar]
  • 139.Pertwee RG. Cannabinoid receptors and pain. Prog Neurobiol. 2001;63:569–611. doi: 10.1016/S0301-0082(00)00031-9. [DOI] [PubMed] [Google Scholar]
  • 140.Walker JM, Hohman AG. Cannabinoid mechanisms of pain suppression. In: Pertwee RG, editor. Cannabinoids, Handbook of Experimental Pharmacolology. Heidelberg, Germany: Springer-Verlag; 2005. pp. 509–54. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0304-3940(96)13308-5. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1097/00001756-199601310-00052. [DOI] [PubMed] [Google Scholar]
  • 143.Richardson JD, Aanonsen L, Hargreaves KM. Hypoactivity of the spinal cannabinoid system results in NMDA-dependent hyperalgesia. J Neurosci. 1998;18:451–457. doi: 10.1523/JNEUROSCI.18-01-00451.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0304-3959(02)00302-0. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1046/j.1460-9568.2000.00929.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1073/pnas.1834309100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1126/science.283.5400.401. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1073/pnas.96.10.5780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1073/pnas.96.25.14228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0304-3959(01)00454-7. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.neuropharm.2004.12.008. [DOI] [PubMed] [Google Scholar]
  • 152.Malan TP, Ibrahim MM, Deng H, et al. CB2 cannabinoid receptor-mediated peripheral antinociception. Pain. 2001;93:239–245. doi: 10.1016/S0304-3959(01)00321-9. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0306-4522(03)00126-X. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1097/00000542-200310000-00031. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1124/jpet.103.060079. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1073/pnas.0409888102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0028-3908(00)00135-0. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/sj.bjp.0706348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 159.Calignano A, La Rana G, Giuffrida A, Piomelli D. Control of pain initiation by endogenous cannabinoids. Nature. 1998;394:277–281. doi: 10.1038/28393. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0014-2999(00)00226-0. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1111/j.1365-2044.2004.03674.x. [DOI] [PubMed] [Google Scholar]
  • 162.Noyes R, Brunk SF, Baram DA, Canter A. Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol. 1975;15:139–143. doi: 10.1002/j.1552-4604.1975.tb02348.x. [DOI] [PubMed] [Google Scholar]
  • 163.Noyes R, Brunk SF, Avery DH, Canter A. Analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther. 1975;18:84–89. doi: 10.1002/cpt197518184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 164.Pertwee RG. Cannabinoids and multiple sclerosis. Pharmacol Ther. 2002;95:165–174. doi: 10.1016/S0163-7258(02)00255-3. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1191/0269215503cr581oa. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0140-6736(03)14738-1. [DOI] [PubMed] [Google Scholar]
  • 167.Gauter B, Rukwied R, Konrad C. Cannabinoid agonists in the treatment of blepharospasm—a case report study. Neuroendocrinol Lett. 2004;25:45–48. [PubMed] [Google Scholar]
  • 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. doi: 10.1191/1352458504ms1063oa. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1136/bmj.38149.566979.AE. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.bmcl.2004.11.007. [DOI] [PubMed] [Google Scholar]
  • 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.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.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. doi: 10.1111/j.1471-4159.2004.02979.x. [DOI] [PubMed] [Google Scholar]
  • 175.Pryce G, Ahmed Z, Hankey DJR, et al. Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain. 2003;126:2191–2202. doi: 10.1093/brain/awg224. [DOI] [PubMed] [Google Scholar]
  • 176.Baker D, Pryce G, Croxford JL, et al. Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature. 2000;404:84–87. doi: 10.1038/35003583. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0014-2999(02)01369-9. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1211/0022357022304. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/0165-5728(89)90075-1. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/0162-3109(94)90056-6. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1172/JCI17652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1523/JNEUROSCI.23-07-02511.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1191/1352458504ms1048oa. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1191/1352458504ms1082oa. [DOI] [PubMed] [Google Scholar]
  • 185.Killestein J, Hoogervorst ELJ, Reif M, et al. Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology. 2002;58:1404–1407. doi: 10.1212/wnl.58.9.1404. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1096/fj.04-1754fje. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1096/fj.01-0320fje. [DOI] [PubMed] [Google Scholar]
  • 188.Bifulco M, Di Marzo V. Targeting the endocannabinoid system in cancer therapy: a call for further research. Nat Med. 2002;8:547–550. doi: 10.1038/nm0602-547. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1096/fj.02-1129fje. [DOI] [PubMed] [Google Scholar]
  • 190.Guzmán M. Cannabinoids: potential anticancer agents. Nat Rev Cancer. 2003;3:745–755. doi: 10.1038/nrc1188. [DOI] [PubMed] [Google Scholar]
  • 191.Guzmán M. Effects on cell viability. In: Pertwee RG, editor. Cannabinoids Handbook of Experimental Pharmacolology. Heidelberg, Germany: Springer-Verlag; 2005. pp. 627–642. [Google Scholar]
  • 192.Izzo AA, Coutts AA. Cannabinoids and the digestive tract. In: Pertwee RG, editor. Cannabinoids, Handbook of Experimental Pharmacolology. Heidelberg, Germany: Springer-Verlag; 2005. pp. 573–598. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/sj.jcbfm.9600047. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.nbd.2004.03.002. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.nbd.2004.10.015. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1007/s002130100728. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/37371. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1093/bja/aei106. [DOI] [PubMed] [Google Scholar]
  • 199.Robson PJ. Human studies of cannabinoids and medicinal cannabis. In: Pertwee RG, editor. Cannabinoids, Handbook Exp Pharmacol. Heidelberg, Germany: Springer-Verlag; 2005. pp. 719–756. [DOI] [PubMed] [Google Scholar]
  • 200.Robson PJ, Guy GW. Clinical studies of cannabis-based medicines. In: Guy GW, Whittle BA, Robson PJ, editors. The Medicinal Uses of Cannabis and Cannabinoids. London, UK: Pharmaceutical Press; 2005. pp. 229–269. [Google Scholar]
  • 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. doi: 10.1159/000112901. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1111/j.1742-1241.2004.00271.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1124/jpet.103.062836. [DOI] [PubMed] [Google Scholar]
  • 204.Rukwied R, Watkinson A, McGlone F, Dvorak M. Cannabinoid agonists attenuate capsaicin-induced responses in human skin. Pain. 2003;102:283–288. doi: 10.1016/S0304-3959(02)00401-3. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1007/s00011-003-1162-z. [DOI] [PubMed] [Google Scholar]
  • 206.Cichewicz DL. Synergistic interactions between cannabinoid and opioid analgesics. Life Sci. 2004;74:1317–1324. doi: 10.1016/j.lfs.2003.09.038. [DOI] [PubMed] [Google Scholar]
  • 207.Holdcroft A, Smith M, Jacklin A, et al. Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia. 1997;52:483–488. doi: 10.1111/j.1365-2044.1997.139-az0132.x. [DOI] [PubMed] [Google Scholar]
  • 208.Pertwee RG. The pharmacology and therapeutic potential of cannabidiol. In: Di Marzo V, editor. Cannabinoids. New York, NY: Kluwer Academic/Plenum Publishers; 2004. pp. 32–83. [Google Scholar]
  • 209.Mendelson WB, Basile AS. The hypnotic actions of the fatty acid amide, oleamide. Neuropsychopharmacology. 2001;25:S36–S39. doi: 10.1016/S0893-133X(01)00341-4. [DOI] [PubMed] [Google Scholar]
  • 210.Pertwee RG, Ross RA. Cannabinoid receptors and their ligands. Prostaglandins Leukot Essent Fatty Acids. 2002;66:101–121. doi: 10.1054/plef.2001.0341. [DOI] [PubMed] [Google Scholar]
  • 211.Sim-Selley LJ. Regulation of cannabinoid CB1 receptors in the central nervous system by chronic cannabinoids. Crit Rev Neurobiol. 2003;15:91–119. doi: 10.1615/CritRevNeurobiol.v15.i2.10. [DOI] [PubMed] [Google Scholar]
  • 212.Lichtman AH, Martin BR. Cannabinoid tolerance and dependence. In: Pertwee RG, editor. Cannabinoids, Handbook of Experimental Pharmacolology. Heidelberg, Germany: Springer-Verlag; 2005. pp. 691–717. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1097/00008877-200402000-00001. [DOI] [PubMed] [Google Scholar]
  • 214.Paria BC, Dey SK. Ligand-receptor signaling with endocannabinoids in preimplantation embryo development and implantation. Chem Phys Lipids. 2000;108:211–220. doi: 10.1016/S0009-3084(00)00197-3. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0140-6736(05)66374-X. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/nm1255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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; Burlington, VT: International Cannabinoid Research Society; 2005. pp. 16–16. [Google Scholar]
  • 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. pp. 106–106. [Google Scholar]
  • 219.Hohmann AG, Suplita RL, Bolton NM, et al. An endocannabinoid mechanism for stress-induced analgesia. Nature. 2005;435:1108–1112. doi: 10.1038/nature03658. [DOI] [PubMed] [Google Scholar]

Articles from The AAPS Journal are provided here courtesy of American Association of Pharmaceutical Scientists

RESOURCES