Abstract
An accumulating body of evidence suggests that endocannabinoids and cannabinoid receptors type 1 and 2 (CB1, CB2) play a significant role in physiologic and pathologic processes, including cognitive and immune functions. While the addictive properties of marijuana, an extract from the Cannabis plant, are well recognized, there is growing appreciation of the therapeutic potential of cannabinoids in multiple pathologic conditions involving chronic inflammation (inflammatory bowel disease, arthritis, autoimmune disorders, multiple sclerosis, HIV-1 infection, stroke, Alzheimer’s disease to name a few), mainly mediated by CB2 activation. Development of CB2 agonists as therapeutic agents has been hampered by the complexity of their intracellular signaling, relative paucity of highly selective compounds and insufficient data regarding end effects in the target cells and organs. This review attempts to summarize recent advances in studies of CB2 activation in the setting of neuroinflammation, immunomodulation and HIV-1 infection.
Similar content being viewed by others
References
Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, Rowbotham MC, Petersen KL (2007) Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 68:515–521
Adhikary S, Kocieda VP, Yen JH, Tuma RF, Ganea D (2012) Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression. Blood 120:3741–3749
Ahn KH, Pellegrini M, Tsomaia N, Yatawara AK, Kendall DA, Mierke DF (2009) Structural analysis of the human cannabinoid receptor one carboxyl-terminus identifies two amphipathic helices. Biopolymers 91:565–573
Anday JK, Mercier RW (2005) Gene ancestry of the cannabinoid receptor family. Pharmacol Res 52:463–466
Ashton CH, Moore PB (2011) Endocannabinoid system dysfunction in mood and related disorders. Acta Psychiatr Scand 124:250–261
Ashton JC, Rahman RM, Nair SM, Sutherland BA, Glass M, Appleton I (2007) Cerebral hypoxia-ischemia and middle cerebral artery occlusion induce expression of the cannabinoid CB2 receptor in the brain. Neurosci Lett 412:114–117
Atwood BK, Straiker A, Mackie K (2012) CB(2): therapeutic target-in-waiting. Prog Neuropsychopharmacol Biol Psychiatry 38:16–20
Azorlosa JL, Heishman SJ, Stitzer ML, Mahaffey JM (1992) Marijuana smoking: effect of varying delta 9-tetrahydrocannabinol content and number of puffs. J Pharmacol Exp Ther 261:114–122
Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Makriyannis A, Khanolkar A, Layward L, Fezza F, Bisogno T, Di Marzo V (2001) Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J 15:300–302
Barbato L (2007) Dronabinol treatment for migraine. In. US
Bari M, Spagnuolo P, Fezza F, Oddi S, Pasquariello N, Finazzi-Agro A, Maccarrone M (2006) Effect of lipid rafts on Cb2 receptor signaling and 2-arachidonoyl-glycerol metabolism in human immune cells. J Immunol 177:4971–4980
Ben Amar M (2006) Cannabinoids in medicine: a review of their therapeutic potential. J Ethnopharmacol 105:1–25
Benito C, Tolon RM, Pazos MR, Nunez E, Castillo AI, Romero J (2008) Cannabinoid CB2 receptors in human brain inflammation. Br J Pharmacol 153:277–285
Benito C, Kim WK, Chavarria I, Hillard CJ, Mackie K, Tolon RM, Williams K, Romero J (2005) A glial endogenous cannabinoid system is upregulated in the brains of macaques with simian immunodeficiency virus-induced encephalitis. J Neurosci 25:2530–2536
Benito C, Romero JP, Tolon RM, Clemente D, Docagne F, Hillard CJ, Guaza C, Romero J (2007) Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis. J Neurosci 27:2396–2402
Berdyshev E, Boichot E, Corbel M, Germain N, Lagente V (1998) Effects of cannabinoid receptor ligands on LPS-induced pulmonary inflammation in mice. Life Sci 63:PL125–PL129
Carissimi M, Gentili P, Grumelli E, Milla E, Picciola G, Ravenna F (1976) Basic ethers of cyclohexylphenols with beta-blocking activity: synthesis and pharmacological study of exaprolol. Arzneimittelforschung 26:506–516
Carlisle SJ, Marciano-Cabral F, Staab A, Ludwick C, Cabral GA (2002) Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. Int Immunopharmacol 2:69–82
Chen Y, Buck J (2000) Cannabinoids protect cells from oxidative cell death: a receptor-independent mechanism. J Pharmacol Exp Ther 293:807–812
Chuchawankul S, Shima M, Buckley NE, Hartmann CB, McCoy KL (2004) Role of cannabinoid receptors in inhibiting macrophage costimulatory activity. Int Immunopharmacol 4:265–278
Condie R, Herring A, Koh WS, Lee M, Kaminski NE (1996) Cannabinoid inhibition of adenylate cyclase-mediated signal transduction and interleukin 2 (IL-2) expression in the murine T-cell line, EL4.IL-2. J Biol Chem 271:13175–13183
Console-Bram L, Marcu J, Abood ME (2012) Cannabinoid receptors: nomenclature and pharmacological principles. Prog Neuropsychopharmacol Biol Psychiatry
Conti S, Costa B, Colleoni M, Parolaro D, Giagnoni G (2002) Antiinflammatory action of endocannabinoid palmitoylethanolamide and the synthetic cannabinoid nabilone in a model of acute inflammation in the rat. Br J Pharmacol 135:181–187
Correa F, Docagne F, Mestre L, Clemente D, Hernangomez M, Loria F, Guaza C (2009) A role for CB2 receptors in anandamide signalling pathways involved in the regulation of IL-12 and IL-23 in microglial cells. Biochem Pharmacol 77:86–100
Costantino CM, Gupta A, Yewdall AW, Dale BM, Devi LA, Chen BK (2012) Cannabinoid receptor 2-mediated attenuation of CXCR4-tropic HIV infection in primary CD4+ T cells. PLoS One 7:e33961
Crandall J, Matragoon S, Khalifa YM, Borlongan C, Tsai NT, Caldwell RB, Liou GI (2007) Neuroprotective and intraocular pressure-lowering effects of (−)Delta9-tetrahydrocannabinol in a rat model of glaucoma. Ophthalmic Res 39:69–75
Crippa JA, Zuardi AW (2006) Duloxetine in the treatment of panic disorder. Int J Neuropsychopharmacol 9:633–634
Dainese E, Oddi S, Maccarrone M (2008) Lipid-mediated dimerization of beta2-adrenergic receptor reveals important clues for cannabinoid receptors. Cell Mol Life Sci 65:2277–2279
Dejesus E, Rodwick BM, Bowers D, Cohen CJ, Pearce D (2007) Use of Dronabinol improves appetite and reverses weight loss in HIV/AIDS-infected patients. J Int Assoc Physicians AIDS Care (Chic) 6:95–100
Derocq JM, Segui M, Marchand J, Le Fur G, Casellas P (1995) Cannabinoids enhance human B-cell growth at low nanomolar concentrations. FEBS Lett 369:177–182
Devane WA, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34:605–613
Docagne F, Muneton V, Clemente D, Ali C, Loria F, Correa F, Hernangomez M, Mestre L, Vivien D, Guaza C (2007) Excitotoxicity in a chronic model of multiple sclerosis: neuroprotective effects of cannabinoids through CB1 and CB2 receptor activation. Mol Cell Neurosci 34:551–561
El-Remessy AB, Tang Y, Zhu G, Matragoon S, Khalifa Y, Liu EK, Liu JY, Hanson E, Mian S, Fatteh N, Liou GI (2008) Neuroprotective effects of cannabidiol in endotoxin-induced uveitis: critical role of p38 MAPK activation. Mol Vis 14:2190–2203
Eljaschewitsch E, Witting A, Mawrin C, Lee T, Schmidt PM, Wolf S, Hoertnagl H, Raine CS, Schneider-Stock R, Nitsch R, Ullrich O (2006) The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron 49:67–79
Engelhardt B, Ransohoff RM (2005) The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol 26:485–495
Facchinetti F, Del Giudice E, Furegato S, Passarotto M, Leon A (2003) Cannabinoids ablate release of TNFalpha in rat microglial cells stimulated with lypopolysaccharide. Glia 41:161–168
Fan P (1995) Cannabinoid agonists inhibit the activation of 5-HT3 receptors in rat nodose ganglion neurons. J Neurophysiol 73:907–910
Felder CC, Joyce KE, Briley EM, Mansouri J, Mackie K, Blond O, Lai Y, Ma AL, Mitchell RL (1995) Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol 48:443–450
Fernandez-Lopez D, Martinez-Orgado J, Nunez E, Romero J, Lorenzo P, Moro MA, Lizasoain I (2006) Characterization of the neuroprotective effect of the cannabinoid agonist WIN-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats. Pediatr Res 60:169–173
Fraga D, Raborn ES, Ferreira GA, Cabral GA (2011) Cannabinoids inhibit migration of microglial-like cells to the HIV protein Tat. J Neuroimmune Pharmacol 6:566–577
Gaoni Y, Mechoulam R (1971) The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish. J Am Chem Soc 93:217–224
Gertsch J, Leonti M, Raduner S, Racz I, Chen JZ, Xie XQ, Altmann KH, Karsak M, Zimmer A (2008) Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci U S A 105:9099–9104
Golech SA, McCarron RM, Chen Y, Bembry J, Lenz F, Mechoulam R, Shohami E, Spatz M (2004) Human brain endothelium: coexpression and function of vanilloid and endocannabinoid receptors. Brain Res Mol Brain Res 132:87–92
Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (−)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A 95:8268–8273
Han KH, Lim S, Ryu J, Lee CW, Kim Y, Kang JH, Kang SS, Ahn YK, Park CS, Kim JJ (2009) CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages. Cardiovasc Res 84:378–386
Heishman SJ, Stitzer ML, Yingling JE (1989) Effects of tetrahydrocannabinol content on marijuana smoking behavior, subjective reports, and performance. Pharmacol Biochem Behav 34:173–179
Howlett AC (2005) Cannabinoid receptor signaling. Handb Exp Pharmacol pp 53–79
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54:161–202
Huestis MA (2007) Human cannabinoid pharmacokinetics. Chem Biodivers 4:1770–1804
Huffman JW, Padgett LW, Isherwood ML, Wiley JL, Martin BR (2006) 1-Alkyl-2-aryl-4-(1-naphthoyl)pyrroles: new high affinity ligands for the cannabinoid CB1 and CB2 receptors. Bioorg Med Chem Lett 16:5432–5435
Huffman JW, Lu J, Dai D, Kitaygorodskiy A, Wiley JL, Martin BR (2000) Synthesis and pharmacology of a hybrid cannabinoid. Bioorg Med Chem 8:439–447
Huffman JW, Hepburn SA, Lyutenko N, Thompson AL, Wiley JL, Selley DE, Martin BR (2010) 1-Bromo-3-(1′,1′-dimethylalkyl)-1-deoxy-Delta(8)-tetrahydrocannabinols: new selective ligands for the cannabinoid CB(2) receptor. Bioorg Med Chem 18:7809–7815
Huffman JW, Yu S, Showalter V, Abood ME, Wiley JL, Compton DR, Martin BR, Bramblett RD, Reggio PH (1996) Synthesis and pharmacology of a very potent cannabinoid lacking a phenolic hydroxyl with high affinity for the CB2 receptor. J Med Chem 39:3875–3877
Huffman JW, Mabon R, Wu MJ, Lu J, Hart R, Hurst DP, Reggio PH, Wiley JL, Martin BR (2003) 3-Indolyl-1-naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB(1) cannabinoid receptor. Bioorg Med Chem 11:539–549
Huffman JW, Zengin G, Wu MJ, Lu J, Hynd G, Bushell K, Thompson AL, Bushell S, Tartal C, Hurst DP, Reggio PH, Selley DE, Cassidy MP, Wiley JL, Martin BR (2005) Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists. Bioorg Med Chem 13:89–112
Karst M, Wippermann S, Ahrens J (2010) Role of cannabinoids in the treatment of pain and (painful) spasticity. Drugs 70:2409–2438
Kim HJ, Shin AH, Thayer SA (2011) Activation of cannabinoid type 2 receptors inhibits HIV-1 envelope glycoprotein gp120-induced synapse loss. Mol Pharmacol 80:357–366
Kim K, Moore DH, Makriyannis A, Abood ME (2006) AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis. Eur J Pharmacol 542:100–105
Klegeris A, Bissonnette CJ, McGeer PL (2003) Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. Br J Pharmacol 139:775–786
Kogan NM, Schlesinger M, Peters M, Marincheva G, Beeri R, Mechoulam R (2007) A cannabinoid anticancer quinone, HU-331, is more potent and less cardiotoxic than doxorubicin: a comparative in vivo study. J Pharmacol Exp Ther 322:646–653
Krymchantowski AV, Jevoux Cda C (2007) The experience of combining agents, specially triptans and non steroidal anti-inflammatory drugs, for the acute treatment of migraine - a review. Recent Pat CNS Drug Discov 2:141–144
Kurihara R, Tohyama Y, Matsusaka S, Naruse H, Kinoshita E, Tsujioka T, Katsumata Y, Yamamura H (2006) Effects of peripheral cannabinoid receptor ligands on motility and polarization in neutrophil-like HL60 cells and human neutrophils. J Biol Chem 281:12908–12918
Lakhan SE, Rowland M (2009) Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review. BMC Neurol 9:59
Law B, Mason PA, Moffat AC, Gleadle RI, King LJ (1984) Forensic aspects of the metabolism and excretion of cannabinoids following oral ingestion of cannabis resin. J Pharm Pharmacol 36:289–294
Lee SF, Newton C, Widen R, Friedman H, Klein TW (2001) Differential expression of cannabinoid CB(2) receptor mRNA in mouse immune cell subpopulations and following B cell stimulation. Eur J Pharmacol 423:235–241
Leussink VI, Husseini L, Warnke C, Broussalis E, Hartung HP, Kieseier BC (2012) Symptomatic therapy in multiple sclerosis: the role of cannabinoids in treating spasticity. Ther Adv Neurol Disord 5:255–266
Liu QR, Pan CH, Hishimoto A, Li CY, Xi ZX, Llorente-Berzal A, Viveros MP, Ishiguro H, Arinami T, Onaivi ES, Uhl GR (2009) Species differences in cannabinoid receptor 2 (CNR2 gene): identification of novel human and rodent CB2 isoforms, differential tissue expression and regulation by cannabinoid receptor ligands. Genes Brain Behav 8:519–530
Lombard C, Nagarkatti M, Nagarkatti P (2007) CB2 cannabinoid receptor agonist, JWH-015, triggers apoptosis in immune cells: potential role for CB2-selective ligands as immunosuppressive agents. Clin Immunol 122:259–270
Louvet A, Teixeira-Clerc F, Chobert MN, Deveaux V, Pavoine C, Zimmer A, Pecker F, Mallat A, Lotersztajn S (2011) Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice. Hepatology 54:1217–1226
Lu TS, Avraham HK, Seng S, Tachado SD, Koziel H, Makriyannis A, Avraham S (2008) Cannabinoids inhibit HIV-1 Gp120-mediated insults in brain microvascular endothelial cells. J Immunol 181:6406–6416
Mahadevan A, Siegel C, Martin BR, Abood ME, Beletskaya I, Razdan RK (2000) Novel cannabinol probes for CB1 and CB2 cannabinoid receptors. J Med Chem 43:3778–3785
Maresz K, Pryce G, Ponomarev ED, Marsicano G, Croxford JL, Shriver LP, Ledent C, Cheng X, Carrier EJ, Mann MK, Giovannoni G, Pertwee RG, Yamamura T, Buckley NE, Hillard CJ, Lutz B, Baker D, Dittel BN (2007) Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat Med 13:492–497
Marsicano G, Lutz B (1999) Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci 11:4213–4225
Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutierrez SO, van der Stelt M, Lopez-Rodriguez ML, Casanova E, Schutz G, Zieglgansberger W, Di Marzo V, Behl C, Lutz B (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302:84–88
Martin-Moreno AM, Brera B, Spuch C, Carro E, Garcia-Garcia L, Delgado M, Pozo MA, Innamorato NG, Cuadrado A, Ceballos ML (2012) Prolonged oral cannabinoid administration prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J Neuroinflammation 9:8
Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564
Maurer M, Henn V, Dittrich A, Hofmann A (1990) Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. Eur Arch Psychiatry Clin Neurosci 240:1–4
McKallip RJ, Lombard C, Martin BR, Nagarkatti M, Nagarkatti PS (2002a) Delta(9)-tetrahydrocannabinol-induced apoptosis in the thymus and spleen as a mechanism of immunosuppression in vitro and in vivo. J Pharmacol Exp Ther 302:451–465
McKallip RJ, Lombard C, Fisher M, Martin BR, Ryu S, Grant S, Nagarkatti PS, Nagarkatti M (2002b) Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 100:627–634
Mechoulam R, Gaoni Y (1965) Hashish. IV. The isolation and structure of cannabinolic cannabidiolic and cannabigerolic acids. Tetrahedron 21:1223–1229
Mechoulam R, Gaoni Y (1967) Recent advances in the chemistry of hashish. Fortschr Chem Org Naturst 25:175–213
Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO (2007) Cannabidiol–recent advances. Chem Biodivers 4:1678–1692
Merighi S, Gessi S, Varani K, Simioni C, Fazzi D, Mirandola P, Borea PA (2011) Cannabinoid CB(2) receptors modulate ERK-1/2 kinase signalling and NO release in microglial cells stimulated with bacterial lipopolysaccharide. Br J Pharmacol 165:1773–1788
Mestre L, Docagne F, Correa F, Loria F, Hernangomez M, Borrell J, Guaza C (2009) A cannabinoid agonist interferes with the progression of a chronic model of multiple sclerosis by downregulating adhesion molecules. Mol Cell Neurosci 40:258–266
Miller AM, Stella N (2008) CB2 receptor-mediated migration of immune cells: it can go either way. Br J Pharmacol 153:299–308
Molina PE, Amedee A, LeCapitaine NJ, Zabaleta J, Mohan M, Winsauer P, Vande Stouwe C (2011) Cannabinoid neuroimmune modulation of SIV disease. J Neuroimmune Pharmacol 6:516–527
Molina PE, Winsauer P, Zhang P, Walker E, Birke L, Amedee A, Stouwe CV, Troxclair D, McGoey R, Varner K, Byerley L, Lamotte L (2010) Cannabinoid Administration Attenuates the Progression of Simian Immunodeficiency Virus. AIDS Res Hum Retroviruses
Molina-Holgado F, Molina-Holgado E, Guaza C (1998) The endogenous cannabinoid anandamide potentiates interleukin-6 production by astrocytes infected with Theiler’s murine encephalomyelitis virus by a receptor-mediated pathway. FEBS Lett 433:139–142
Montecucco F, Burger F, Mach F, Steffens S (2008) CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways. Am J Physiol Heart Circ Physiol 294:H1145–H1155
Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65
Murikinati S, Juttler E, Keinert T, Ridder DA, Muhammad S, Waibler Z, Ledent C, Zimmer A, Kalinke U, Schwaninger M (2010) Activation of cannabinoid 2 receptors protects against cerebral ischemia by inhibiting neutrophil recruitment. FASEB J 24:788–798
Nunez E, Benito C, Pazos MR, Barbachano A, Fajardo O, Gonzalez S, Tolon RM, Romero J (2004) Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse 53:208–213
Offertaler L, Mo FM, Batkai S, Liu J, Begg M, Razdan RK, Martin BR, Bukoski RD, Kunos G (2003) Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor. Mol Pharmacol 63:699–705
Pacher P, Batkai S, Kunos G (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58:389–462
Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289:739–745
Panikashvili D, Shein NA, Mechoulam R, Trembovler V, Kohen R, Alexandrovich A, Shohami E (2006) The endocannabinoid 2-AG protects the blood–brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines. Neurobiol Dis 22:257–264
Persidsky Y, Ho W, Ramirez SH, Potula R, Abood ME, Unterwald E, Tuma R (2011) HIV-1 infection and alcohol abuse: neurocognitive impairment, mechanisms of neurodegeneration and therapeutic interventions. Brain Behav Immun 25(Suppl 1):S61–S70
Peterson PK, Gekker G, Hu S, Cabral G, Lokensgard JR (2004) Cannabinoids and morphine differentially affect HIV-1 expression in CD4(+) lymphocyte and microglial cell cultures. J Neuroimmunol 147:123–126
Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J (2006) Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 295:761–775
Pini A, Mannaioni G, Pellegrini-Giampietro D, Passani MB, Mastroianni R, Bani D, Masini E (2012) The role of cannabinoids in inflammatory modulation of allergic respiratory disorders, inflammatory pain and ischemic stroke. Curr Drug Targets 13:984–993
Pryce G, Baker D (2005) Emerging properties of cannabinoid medicines in management of multiple sclerosis. Trends Neurosci 28:272–276
Puffenbarger RA, Boothe AC, Cabral GA (2000) Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells. Glia 29:58–69
Racz I, Nadal X, Alferink J, Banos JE, Rehnelt J, Martin M, Pintado B, Gutierrez-Adan A, Sanguino E, Bellora N, Manzanares J, Zimmer A, Maldonado R (2008) Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain. J Neurosci 28:12136–12145
Rajesh M, Mukhopadhyay P, Batkai S, Hasko G, Liaudet L, Huffman JW, Csiszar A, Ungvari Z, Mackie K, Chatterjee S, Pacher P (2007) CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. Am J Physiol Heart Circ Physiol 293:H2210–H2218
Ramirez BG, Blazquez C, Gomez del Pulgar T, Guzman M, de Ceballos ML (2005) Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci 25:1904–1913
Ramirez SH, Hasko J, Skuba A, Fan S, Dykstra H, McCormick R, Reichenbach N, Krizbai I, Mahadevan A, Zhang M, Tuma R, Son YJ, Persidsky Y (2012) Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood–brain barrier dysfunction under inflammatory conditions. J Neurosci 32:4004–4016
Rieder SA, Chauhan A, Singh U, Nagarkatti M, Nagarkatti P (2010) Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression. Immunobiology 215:598–605
Ronco AM, Llanos M, Tamayo D, Hirsch S (2007) Anandamide inhibits endothelin-1 production by human cultured endothelial cells: a new vascular action of this endocannabinoid. Pharmacology 79:12–16
Russo EB, Guy GW, Robson PJ (2007) Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem Biodivers 4:1729–1743
Ryberg E, Vu HK, Larsson N, Groblewski T, Hjorth S, Elebring T, Sjogren S, Greasley PJ (2005) Identification and characterisation of a novel splice variant of the human CB1 receptor. FEBS Lett 579:259–264
Sanchez AJ, Garcia-Merino A (2011) Neuroprotective agents: cannabinoids. Clin Immunol 142:57–67
Sarfaraz S, Adhami VM, Syed DN, Afaq F, Mukhtar H (2008) Cannabinoids for cancer treatment: progress and promise. Cancer Res 68:339–342
Sastre-Garriga J, Vila C, Clissold S, Montalban X (2007) THC and CBD oromucosal spray (Sativex(R)) in the management of spasticity associated with multiple sclerosis. Expert Rev Neurother 11:627–637
Schwarz H, Blanco FJ, Lotz M (1994) Anadamide, an endogenous cannabinoid receptor agonist inhibits lymphocyte proliferation and induces apoptosis. J Neuroimmunol 55:107–115
Shoemaker JL, Ruckle MB, Mayeux PR, Prather PL (2005) Agonist-directed trafficking of response by endocannabinoids acting at CB2 receptors. J Pharmacol Exp Ther 315:828–838
Solas M, Francis PT, Franco R, Ramirez MJ (2012) CB(2) receptor and amyloid pathology in frontal cortex of Alzheimer’s disease patients. Neurobiol Aging
Storr MA, Keenan CM, Zhang H, Patel KD, Makriyannis A, Sharkey KA (2009) Activation of the cannabinoid 2 receptor (CB2) protects against experimental colitis. Inflamm Bowel Dis 15:1678–1685
Tao Q, McAllister SD, Andreassi J, Nowell KW, Cabral GA, Hurst DP, Bachtel K, Ekman MC, Reggio PH, Abood ME (1999) Role of a conserved lysine residue in the peripheral cannabinoid receptor (CB2): evidence for subtype specificity. Mol Pharmacol 55:605–613
Todaro B (2012) Cannabinoids in the treatment of chemotherapy-induced nausea and vomiting. J Natl Compr Canc Netw 10:487–492
Tschop J, Kasten KR, Nogueiras R, Goetzman HS, Cave CM, England LG, Dattilo J, Lentsch AB, Tschop MH, Caldwell CC (2009) The cannabinoid receptor 2 is critical for the host response to sepsis. J Immunol 183:499–505
Tuma RF, Steffens S (2012) Targeting the endocannabinod system to limit myocardial and cerebral ischemic and reperfusion injury. Curr Pharm Biotechnol 13:46–58
Tzavara ET, Davis RJ, Perry KW, Li X, Salhoff C, Bymaster FP, Witkin JM, Nomikos GG (2003) The CB1 receptor antagonist SR141716A selectively increases monoaminergic neurotransmission in the medial prefrontal cortex: implications for therapeutic actions. Br J Pharmacol 138:544–553
Viscomi MT, Oddi S, Latini L, Pasquariello N, Florenzano F, Bernardi G, Molinari M, Maccarrone M (2009) Selective CB2 receptor agonism protects central neurons from remote axotomy-induced apoptosis through the PI3K/Akt pathway. J Neurosci 29:4564–4570
Wiley JL, Compton DR, Dai D, Lainton JA, Phillips M, Huffman JW, Martin BR (1998) Structure-activity relationships of indole- and pyrrole-derived cannabinoids. J Pharmacol Exp Ther 285:995–1004
Williams PB, Martin BR, Lattanzio FA, Samudre S, Razdan RK (2007) Novel cannabinoids and methods of use. In
Witkin JM, Tzavara ET, Davis RJ, Li X, Nomikos GG (2005) A therapeutic role for cannabinoid CB1 receptor antagonists in major depressive disorders. Trends Pharmacol Sci 26:609–617
Woelkart K, Salo-Ahen OM, Bauer R (2008) CB receptor ligands from plants. Curr Top Med Chem 8:173–186
Xiao JC, Jewell JP, Lin LS, Hagmann WK, Fong TM, Shen CP (2008) Similar in vitro pharmacology of human cannabinoid CB1 receptor variants expressed in CHO cells. Brain Res 1238:36–43
Xie XQ, Chen JZ (2005) NMR structural comparison of the cytoplasmic juxtamembrane domains of G-protein-coupled CB1 and CB2 receptors in membrane mimetic dodecylphosphocholine micelles. J Biol Chem 280:3605–3612
Xie XQ, Chen JZ, Billings EM (2003) 3D structural model of the G-protein-coupled cannabinoid CB2 receptor. Proteins 53:307–319
Yao B, Mackie K (2009) Endocannabinoid receptor pharmacology. Curr Top Behav Neurosci 1:37–63
Yazulla S (2008) Endocannabinoids in the retina: from marijuana to neuroprotection. Prog Retin Eye Res 27:501–526
Yiangou Y, Facer P, Durrenberger P, Chessell IP, Naylor A, Bountra C, Banati RR, Anand P (2006) COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol 6:12
Yu XH, Cao CQ, Martino G, Puma C, Morinville A, St-Onge S, Lessard E, Perkins MN, Laird JM (2010) A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain. Pain 151:337–344
Zhang M, Martin BR, Adler MW, Razdan RK, Jallo JI, Tuma RF (2007) Cannabinoid CB(2) receptor activation decreases cerebral infarction in a mouse focal ischemia/reperfusion model. J Cereb Blood Flow Metab 27:1387–1396
Zhang M, Adler MW, Abood ME, Ganea D, Jallo J, Tuma RF (2009) CB2 receptor activation attenuates microcirculatory dysfunction during cerebral ischemic/reperfusion injury. Microvasc Res 78:86–94
Zhu W, Friedman H, Klein TW (1998) Delta9-tetrahydrocannabinol induces apoptosis in macrophages and lymphocytes: involvement of Bcl-2 and caspase-1. J Pharmacol Exp Ther 286:1103–1109
Ziring D, Wei B, Velazquez P, Schrage M, Buckley NE, Braun J (2006) Formation of B and T cell subsets require the cannabinoid receptor CB2. Immunogenetics 58:714–725
Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimaraes FS (2006a) Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 39:421–429
Zuardi AW, Hallak JE, Dursun SM, Morais SL, Sanches RF, Musty RE, Crippa JA (2006b) Cannabidiol monotherapy for treatment-resistant schizophrenia. J Psychopharmacol 20:683–686
Acknowledgements
This work was supported in part by NIH Grants AA017398, MH065151, DA025566, and AA015913 (Y.P.). The authors express their grateful acknowledgement for proofreading and editing to Nancy L. Reichenbach.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Rom, S., Persidsky, Y. Cannabinoid Receptor 2: Potential Role in Immunomodulation and Neuroinflammation. J Neuroimmune Pharmacol 8, 608–620 (2013). https://doi.org/10.1007/s11481-013-9445-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11481-013-9445-9