Skip to main content
SpringerLink
Log in

Cannabinoid Signaling Through Non-CB1R/Non-CB2R Targets in Microglia

  • Chapter
  • First Online:
endoCANNABINOIDS

Part of the book series: The Receptors ((REC,volume 24))

Abstract

Several Cannabis constituents, including the psychoactive Δ9-tetrahydrocannabinol and the non-psychoactive cannabidiol, exert anti-inflammatory and anti-neurodegenerative effects in various experimental models. Here we review the interaction of cannabinoids (plant, endogenous or synthetic) with microglia, which are considered to be the immune cells of the brain. We describe the functional endocannabinoid system (ligands, receptors, and enzymes) in microglial cell models. In addition, we review the activity of cannabinoid ligands at non-CB1/non-CB2 GPCR targets, mainly GPR55 and GPR18, with focus on microglia. Finally, we discuss non-CB1/non-CB2-mediated effects of cannabinoid ligands on microglial migration, transcriptional regulation, and anti-inflammation in a multiple sclerosis-like model.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Anavi-Goffer S, Baillie G, Irving AJ, Gertsch J, Greig IR, Pertwee RG, Ross RA (2012) Modulation of L-α-lysophosphatidylinositol/GPR55 mitogen-activated protein kinase (MAPK) signaling by cannabinoids. J Biol Chem 287(1):91–104

    Article  PubMed  CAS  Google Scholar 

  • Andradas C, Caffarel MM, Perez-Gomez E, Salazar M, Lorente M, Velasco G, Guzman M, Sanchez C (2011) The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK. Oncogene 30:245–252

    Article  PubMed  CAS  Google Scholar 

  • Aneetha H, O’Dell DK, Tan B, Walker JM, Hurley TD (2009) Alcohol dehydrogenase-catalyzed in vitro oxidation of anandamide to N-arachidonoyl glycine, a lipid mediator: synthesis of N-acyl glycinals. Bioorg Med Chem Lett 19(1):237–241

    Article  PubMed  CAS  Google Scholar 

  • Baker D, Pryce G, Davies WL, Hiley CR (2006) In silico patent searching reveals a new cannabinoid receptor. Trends Pharmacol Sci 27:1–4

    Article  PubMed  CAS  Google Scholar 

  • Balenga NAB, Henstridge CM, Kargl J, Waldhoer M (2011a) Pharmacology, signaling and physiological relevance of the G protein-couple receptor 55. Adv Pharmacol 62:251–277

    Article  PubMed  CAS  Google Scholar 

  • Balenga NAB, Aflaki E, Kargl J, Platzer W, Schröder R, Blättermann S, Kostenis E, Brown AJ, Heinemann A, Waldhoer M (2011b) GPR55 regulates cannabinoid 2-mediated responses in human neutrophils. Cell Res 21(10):1452–1469. doi:10.1038/cr.2011.60

    Article  PubMed  CAS  Google Scholar 

  • Barbara G, Alloui A, Nargeot J, Lory P, Eschalier A, Bourinet E, Chemin J (2009) T-type calcium channel inhibition underlies the analgesic effects of the endogenous lipoamino acids. J Neurosci 29(42):13106–13114

    Article  PubMed  CAS  Google Scholar 

  • Benita Y, Cao Z, Giallourakis C, Li C, Gardet A, Xavier RJ (2010) Gene enrichment profiles reveal T-cell development, differentiation, and lineage-specific transcription factors including ZBTB25 as a novel NF-AT repressor. Blood 115(26):5376–5384

    Article  PubMed  CAS  Google Scholar 

  • Benito C, Romero JP, Tolón 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

    Article  PubMed  CAS  Google Scholar 

  • Berdyshev EV (2000) Cannabinoid receptors and the regulation of immune response. Chem Phys Lipids 108:169–190

    Article  PubMed  CAS  Google Scholar 

  • Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, Moriello AS, Davis JB, Mechoulam R, Di Marzo V (2001) Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 134(4):845–852

    Article  PubMed  CAS  Google Scholar 

  • Blankman JL, Simon GM, Cravatt BF (2007) A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol 14(12):1347–1356

    Article  PubMed  CAS  Google Scholar 

  • Blasi E, Barluzzi R, Bocchini V, Mazzolla R, Bistoni F (1990) Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol 27:229–237

    Article  PubMed  CAS  Google Scholar 

  • Bocchini V, Mazzolla R, Barluzzi R, Blasi E, Sick P, Kettenmann H (1992) An immortalized cell line expresses properties of activated microglial cells. J Neurosci Res 31:616–621

    Article  PubMed  CAS  Google Scholar 

  • Bradshaw HB, Rimmerman N, Hu SS, Benton VM, Stuart JM, Masuda K, Cravatt BF, O’Dell DK, Walker JM (2009a) The endocannabinoid anandamide is a precursor for the signaling lipid N-arachidonoyl glycine by two distinct pathways. BMC Biochem 10:14

    Article  PubMed  CAS  Google Scholar 

  • Bradshaw HB, Lee SH, McHugh D (2009b) Orphan endogenous lipids and orphan GPCRs: a good match. Prostaglandins Other Lipid Mediat 89(3–4):131–134

    Article  PubMed  CAS  Google Scholar 

  • Breivogel CS, Griffin G, Di Marzo V, Martin BR (2001) Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol Pharmacol 60:155–163

    PubMed  CAS  Google Scholar 

  • Brown AJ, Wise A (2001) Glaxosmithkline. Identification of modulators of GPR55 activity. Patent WO0186305

    Google Scholar 

  • Burstein S, Salmonsen R (2008) Acylamido analogs of endocannabinoids selectively inhibit cancer cell proliferation. Bioorg Med Chem 16(22):9644–9651

    Article  PubMed  CAS  Google Scholar 

  • Burstein SH, Rossetti RG, Yagen B, Zurier RB (2000) Oxidative metabolism of anandamide. Prostaglandins Other Lipid Mediat 61(1–2):29–41

    Article  PubMed  CAS  Google Scholar 

  • Burstein SH, Huang SM, Petros TJ, Rossetti RG, Walker JM, Zurier RB (2002) Regulation of anandamide tissue levels by N-arachidonylglycine. Biochem Pharmacol 64(7):1147–1150

    Article  PubMed  CAS  Google Scholar 

  • Cabral GA, Griffin-Thomas L (2009) Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation. Expert Rev Mol Med 11:e3

    Article  PubMed  Google Scholar 

  • Cabral GA, Marciano-Cabral F (2005) Cannabinoid receptors in microglia of the central nervous system: immune functional relevance. J Leukoc Biol 78:1192–1197

    Article  PubMed  CAS  Google Scholar 

  • Cabral GA, Staab A (2005) Effects on the immune system. Handb Exp Pharmacol 168:385–423

    Article  PubMed  CAS  Google Scholar 

  • Cabral GA, Raborn ES, Griffin L, Dennis J, Marciano-Cabral F (2008) CB2 receptors in the brain: role in central immune function. Br J Pharmacol 153:240–251

    Article  PubMed  CAS  Google Scholar 

  • Cadas H, Gaillet S, Beltramo M, Venance L, Piomelli D (1996) Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by calcium and cAMP. J Neurosci 16(12):3934–3942

    PubMed  CAS  Google Scholar 

  • Calignano A, La Rana G, Giuffrida A, Piomelli D (1998) Control of pain initiation by endogenous cannabinoids. Nature 394(6690):277–281

    Article  PubMed  CAS  Google Scholar 

  • Capasso R, Borrelli F, Aviello G, Romano B, Scalisi C, Capasso F, Izzo AA (2008) Cannabidiol extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice. Br J Pharmacol 154(5):1001–1008

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Carrier EJ, Kearn CS, Barkmeier AJ, Breese NM, Yang W, Nithipatikom K, Pfister SL, Campbell WB, Hillard CJ (2004) Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism. Mol Pharmacol 65(4):999–1007

    Article  PubMed  CAS  Google Scholar 

  • Chan WY, Kohsaka S, Rezaie P (2007) The origin and cell lineage of microglia—new concepts. Brain Res Rev 53:344–354

    Article  PubMed  CAS  Google Scholar 

  • Chiba T, Ueno S, Obara Y, Nakahata N (2011) A synthetic cannabinoid, CP55940, inhibits lipopolysaccharide-induced cytokine mRNA expression in a cannabinoid receptor-independent mechanism in rat cerebellar granule cells. J Pharm Pharmacol 63:636–647

    Article  PubMed  CAS  Google Scholar 

  • Correa F, Hernangomez M, Mestre L, Loria F, Spagnolo A, Docagne F, Di Marzo V, Guaza C (2010) Anandamide enhances IL-10 production in activated microglia by targeting CB(2) receptors: roles of ERK1/2, JNK, and NF-kappaB. Glia 58(2):135–147

    Article  PubMed  Google Scholar 

  • Curran NM, Griffin BD, O’Toole D, Brady KJ, Fitzgerald SN, Moynagh PN (2005) The synthetic cannabinoid R(+)WIN55,212-2 inhibits the interleukin-1 signaling pathway in human astrocytes in a cannabinoid receptor-independent manner. J Biol Chem 280:35797–35806

    Article  PubMed  CAS  Google Scholar 

  • Daiyasu H, Osaka K, Ishino Y, Toh H (2001) Expansion of the zinc metallo-hydrolase family of the beta-lactamase fold. FEBS Lett 503(1):1–6

    Article  PubMed  CAS  Google Scholar 

  • Davoust N, Vuaillat C, Androdias G, Natal S (2008) From bone marrow to microglia: barriers and avenues. Trends Immunol 29:227–234

    Article  PubMed  CAS  Google Scholar 

  • De Filippis D, Russo A, De Stefano D, Maiuri MC, Esposito G, Cinelli MP, Pietropaolo C, Carnuccio R, Russo G, Iuvone T (2007) Local administration of WIN55,212-2 reduces chronic granuloma-associated angiogenesis in rat by inhibiting NF-kappaB activation. J Mol Med (Berl) 85:635–645

    Article  CAS  Google Scholar 

  • De Jong EK, de Haas AH, Brouwer N, van Weering HRJ, Hensens M, Bechmann I, Pratley P, Wesseling E, Boddeke HWGM, Biber K (2008) Expression of CXCL4 in microglia in vitro and in vivo and its possible signaling through CXCR3. J Neurochem 105:1726–1736

    Article  PubMed  CAS  Google Scholar 

  • De Petrocellis L, Di Marzo V (2010) Non-CB1, non-CB2 receptors for endocannabinoids, plant cannabinoids and synthetic cannabimimetics: focus on G-protein-coupled receptors and transient receptor potential channels. J Neuroimmune Pharmacol 5:103–121

    Article  PubMed  Google Scholar 

  • Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949

    Article  PubMed  CAS  Google Scholar 

  • Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz JC, Piomelli D (1994) Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372(6507):686–691

    Article  PubMed  Google Scholar 

  • Di Marzo V, Bisogno T, De Petrocellis L (2001) Anandamide: some like it hot. Trends Pharmacol Sci 22(7):346–349

    Article  PubMed  Google Scholar 

  • Drmota T, Greasley P, Groblewski T (2004) AstraZeneca. Screening assays for cannabinoid-ligand type modulators of GPR55. Patent WO2004074844

    Google Scholar 

  • Edington AR, McKinzie AA, Reynolds AJ, Kassiou M, Ryan RM, Vandenberg RJ (2009) Extracellular loops 2 and 4 of GLYT2 are required for N-arachidonylglycine inhibition of glycine transport. J Biol Chem 284(52):36424–36430

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Esposito G, De Filippis D, Maiuri MC, De Stefano D, Carnuccio R, Iuvone T (2006) Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in beta-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-kappaB involvement. Neurosci Lett 399:91–95

    Article  PubMed  CAS  Google Scholar 

  • Evans AT, Formukong E, Evans FJ (1987) Activation of phospholipase A2 by cannabinoids. Lack of correlation with CNS effects. FEBS Lett 211(2):119–122

    Article  PubMed  CAS  Google Scholar 

  • Facchinetti F, del Giudice E, Furegato S, Passarotto M, Leon A (2003) Cannabinoids ablate release of TNFα in rat microglial cells stimulated with lipopolysaccharide. Glia 41:161–168

    Article  PubMed  Google Scholar 

  • Felder CC, Veluz JS, Williams HL, Briley EM, Matsuda LA (1992) Cannabinoid agonists stimulate both receptor- and non receptor-mediated signal transduction pathways in cells transfected with and expressing cannabinoid receptor clones. Mol Pharmacol 42:838–845

    PubMed  CAS  Google Scholar 

  • Fiskerstrand T, H’Mida-Ben Brahim D, Johansson S, M’Zahem A, Haukanes BI, Drouot N, Zimmermann J, Cole AJ, Vedeler C, Bredrup C, Assoum M, Tazir M, Klockgether T, Hamri A, Steen VM, Boman H, Bindoff LA, Koenig M, Knappskog PM (2010) Mutations in ABHD12 cause the neurodegenerative disease PHARC: an inborn error of endocannabinoid metabolism. Am J Hum Genet 87(3):410–417

    Article  PubMed  CAS  Google Scholar 

  • 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(4):566–577

    Article  PubMed  Google Scholar 

  • Franklin A, Stella N (2003) Arachidonylcyclopropylamide increases microglial cell migration through cannabinoid CB2 and abnormal-cannabidiol-sensitive receptors. Eur J Pharmacol 474(2–3):195–198

    Article  PubMed  CAS  Google Scholar 

  • Franklin A, Parmentier-Batteur S, Walter L, Greenberg DA, Stella N (2003) Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. J Neurosci 23(21):7767–7775

    PubMed  CAS  Google Scholar 

  • Fu J, Gaetani S, Oveisi F, Lo Verme J, Serrano A, Rodriguez De Fonseca F, Rosengarth A, Luecke H, Di Giacomo B, Tarzia G, Piomelli D (2003) Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 425(6953):90–93

    Article  PubMed  CAS  Google Scholar 

  • Fu J, Oveisi F, Gaetani S, Lin E, Piomelli D (2005) Oleoylethanolamide, an endogenous PPAR-alpha agonist, lowers body weight and hyperlipidemia in obese rats. Neuropharmacology 48(8):1147–1153

    Article  PubMed  CAS  Google Scholar 

  • Gantz I, Muraoka A, Yang YK, Samuelson LC, Zimmerman EM, Cook H, Yamada T (1997) Cloning and chromosomal localization of a gene (GPR18) encoding a novel seven transmembrane receptor highly expressed in spleen and testis. Genomics 42(3):462–466

    Article  PubMed  CAS  Google Scholar 

  • Gay NJ, Gangloff M (2007) Structure and function of Toll receptors and their ligands. Annu Rev Biochem 76:141–165

    Article  PubMed  CAS  Google Scholar 

  • Giang DK, Cravatt BF (1997) Molecular characterization of human and mouse fatty acid amide hydrolases. Proc Natl Acad Sci U S A 94(6):2238–2242

    Article  PubMed  CAS  Google Scholar 

  • Godlewski G, Offertaler L, Wagner JA, Kunos G (2009) Receptors for acylethanolamides-GPR55 and GPR119. Prostaglandins Other Lipid Mediat 89(3–4):105–111

    Article  PubMed  CAS  Google Scholar 

  • Graeber MB, Streit WJ (2010) Microglia: biology and pathology. Acta Neuropathol 119:89–105

    Article  PubMed  Google Scholar 

  • Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394

    Article  PubMed  CAS  Google Scholar 

  • Hansen HS (2010) Palmitoylethanolamide and other anandamide congeners. Proposed role in the diseased brain. Exp Neurol 224(1):48–55

    Article  PubMed  CAS  Google Scholar 

  • Hansen HS, Lauritzen L, Strand AM, Moesgaard B, Frandsen A (1995) Glutamate stimulates the formation of N-acylphosphatidylethanolamine and N-acylethanolamine in cortical neurons in culture. Biochim Biophys Acta 1258(3):303–308

    Article  PubMed  Google Scholar 

  • Hansen HS, Moesgaard B, Hansen HH, Petersen G (2000) N-Acylethanolamines and precursor phospholipids—relation to cell injury. Chem Phys Lipids 108(1–2):135–150

    Article  PubMed  CAS  Google Scholar 

  • Hansen HS, Moesgaard B, Hansen HH, Petersen G (2001) When and where are N-acylethanolamine phospholipids and anandamide formed? World Rev Nutr Diet 88:223–227

    Article  PubMed  CAS  Google Scholar 

  • Häusler KG, Prinz M, Nolte C, Weber JR, Schumann RR, Kettenmann H, Hanisch U-K (2002) Interferon-γ differentially modulates the release of cytokines and chemokines in lipopolysaccharide- and pneumococcal cell wall-stimulated mouse microglia and macrophages. Eur J Neurosci 16:2113–2122

    Article  PubMed  Google Scholar 

  • Henstridge CM, Balenga NA, Ford LA, Ross RA, Waldhoer M, Irving AJ (2009) The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation. FASEB J 23:183–193

    Article  PubMed  CAS  Google Scholar 

  • Henstridge CM, Balenga NA, Schröder R, Kargl JK, Platzer W, Martini L, Arthur S, Penman J, Whistler JL, Kostenis E, Waldhoer M, Irving AJ (2010) GPR55 ligands promote receptor coupling to multiple signalling pathways. Br J Pharmacol 160:604–614

    Article  PubMed  CAS  Google Scholar 

  • Heppner FL, Greter M, Marino D, Falsig J, Raivich G, Hövelmeyer N, Waisman A, Rülicke T, Prinz M, Priller J, Becher B, Aguzzi A (2005) Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 11(2):146–152

    Article  PubMed  CAS  Google Scholar 

  • Herring AC, Kaminski NE (1999) Cannabinol-mediated inhibition of nuclear factor-kappaB, cAMP response element-binding protein and interleukin-2 secretion by activated thymocytes. J Pharmacol Exp Ther 291:1156–1163

    PubMed  CAS  Google Scholar 

  • Horvath RJ, Nutile-McMenemy N, Alkaitis MS, DeLeo JA (2008) Differential migration, LPS-induced cytokine, chemokine and NO expression in immortalized BV-2 and HAPI cell lines and primary microglial cultures. J Neurochem 107:557–569

    Article  PubMed  CAS  Google Scholar 

  • Howlett AC (2005) Cannabinoid receptor signaling. Handb Exp Pharmacol 168:53–79

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Huang SM, Bisogno T, Petros TJ, Chang SY, Zavitsanos PA, Zipkin RE, Sivakumar R, Coop A, Maeda DY, De Petrocellis L, Burstein S, Di Marzo V, Walker JM (2001) Identification of a new class of molecules, the arachidonyl amino acids, and characterization of one member that inhibits pain. J Biol Chem 276(46):42639–42644

    Article  PubMed  CAS  Google Scholar 

  • Hudson BD, Hebert TE, Kelly ME (2010) Ligand- and herterodimer-directed signaling of the CB(1) cannabinoid receptor. Mol Pharmacol 77:1–9

    Article  PubMed  CAS  Google Scholar 

  • Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 30:515–527

    Article  PubMed  CAS  Google Scholar 

  • Jeon YJ, Yang KH, Pulaski JT, Kaminski NE (1996) Attenuation of inducible nitric oxide synthase gene expression by delta 9-tetrahydrocannabinol is mediated through the inhibition of nuclease factor-kappa B/Rel activation. Mol Pharmacol 50:334–341

    PubMed  CAS  Google Scholar 

  • Johns DG, Behm DJ, Walker DJ, Ao Z, Shapland EM, Daniels DA, Riddick M, Dowell S, Staton PC, Green P, Shabon U, Bao W, Aiyar N, Yue TL, Brown AJ, Morrison AD, Douglas SA (2007) The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects. Br J Pharmacol 152:825–831

    Article  PubMed  CAS  Google Scholar 

  • Juknat A, Rimmerman N, Levy R, Vogel Z, Kozela, E (2011) Cannabidiol affects the expression of genes involved in zinc homeostasis in BV-2 microglial cells. Neurochem Int. 2011 Dec 9. [Epub ahead of print] PMID: 22178458

    Google Scholar 

  • Juknat A, Pietr M, Kozela E, Rimmerman N, Levy R, Coppola G, Geschwind D, Vogel Z (2012) Differential transcriptional profiles mediated by exposure to cannabinoids cannabidiol and Δ-9 tetrahydrocannabinol in BV-2 microglial cells. Br J Pharmacol 165:2512–2528

    Google Scholar 

  • Kapitein B, Hoekstra MO, Nijhuis EH, Hijnen DJ, Arets HG, Kimpen JL, Knol EF (2008) Gene expression in CD4+ T-cells reflects heterogeneity in infant wheezing phenotypes. Eur Respir J 32(5):1203–1212

    Article  PubMed  CAS  Google Scholar 

  • Kaplan BL, Rockwell CE, Kaminski NE (2003) Evidence for cannabinoid receptor-dependent and -independent mechanisms of action in leukocytes. J Pharmacol Exp Ther 306:1077–1085

    Article  PubMed  CAS  Google Scholar 

  • Kapur A, Zhao P, Sharir H, Bai Y, Caron MG, Barak LS, Abood ME (2009) Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands. J Biol Chem 284:29817–29827

    Article  PubMed  CAS  Google Scholar 

  • Karmaus PW, Chen W, Kaplan BL, Kaminski NE (2011) Δ(9)-tetrahydrocannabinol suppresses cytotoxic T lymphocyte function independent of CB1 and CB2, disrupting early activation events. J Neuroimmune Pharmacol.doi: 10.1007/s11481-011-9293-4

  • Kawai T, Takeuchi O, Fujita T, Inoue J, Mühlradt PF, Sato S, Hoshino K, Akira S (2001) Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol 167:5887–5894

    PubMed  CAS  Google Scholar 

  • Kenakin T (2001) Inverse, protean and ligand-selective agonism: matters of receptor conformation. FASEB J 15:598–611

    Article  PubMed  CAS  Google Scholar 

  • Kenakin T (2009) 7TM receptor allostery: putting numbers to shape shifting proteins. Trends Pharmacol Sci 30:460–469

    Article  PubMed  CAS  Google Scholar 

  • Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91(2):461–553

    Article  PubMed  CAS  Google Scholar 

  • Kim SH, Smith CJ, Van Eldik LJ (2004) Importance of MAPK pathways for microglia ­pro-inflammatory cytokine IL-1β production. Neurobiol Aging 25:431–439

    Article  PubMed  CAS  Google Scholar 

  • Kohno M, Hasegawa H, Inoue A, Muraoka M, Miyazaki T, Oka K, Yasukawa M (2006) Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18. Biochem Biophys Res Commun 347(3):827–832

    Article  PubMed  CAS  Google Scholar 

  • Koning N, Uitdehaag BM, Huitinga I, Hoek RM (2009) Restoring immune suppression in the multiple sclerosis brain. Prog Neurobiol 89(4):359–368

    Article  PubMed  CAS  Google Scholar 

  • Kotsikorou E, Madrigal KE, Hurst DP, Sharir H, Lynch DL, Heynen-Genel S, Milan LB, Chung TD, Seltzman HH, Bai Y, Caron MG, Barak L, Abood ME, Reggio PH (2011) Identification of the GPR55 agonist binding site using a novel set of high-potency GPR55 selective ligands. Biochemistry 50:5633–5647

    Article  PubMed  CAS  Google Scholar 

  • Kozela E, Pietr M, Juknat A, Rimmerman N, Levy R, Vogel Z (2010) Cannabinoids Delta(9)-tetrahydrocannabinol and cannabidiol differentially inhibit the lipopolysaccharide-activated NF-kappaB and interferon-beta/STAT proinflammatory pathways in BV-2 microglial cells. J Biol Chem 285(3):1616–1626

    Article  PubMed  CAS  Google Scholar 

  • Kozela E, Lev N, Kaushansky N, Eilam R, Rimmerman N, Levy R, Ben-Nun A, Juknat A, Vogel Z (2011) Cannabidiol inhibits pathogenic T-cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in mice. Br J Pharmacol 163:1507–1519

    Article  PubMed  CAS  Google Scholar 

  • Kreutz S, Koch M, Bottger C, Ghadban C, Korf HW, Dehghani F (2009) 2-Arachidonoylglycerol elicits neuroprotective effects on excitotoxically lesioned dentate gyrus granule cells via abnormal-cannabidiol-sensitive receptors on microglial cells. Glia 57(3):286–294

    Article  PubMed  Google Scholar 

  • Kuehl FA, Jacob TA, Ganley OH, Ormond RE, Meisinger MAP (1957) The identification of N-(2-hydroxyethyl)-palmitamide as a naturally occurring anti-inflammatory agent. J Am Chem Soc 79:5577–5578

    Article  CAS  Google Scholar 

  • Kurahashi Y, Ueda N, Suzuki H, Suzuki M, Yamamoto S (1997) Reversible hydrolysis and synthesis of anandamide demonstrated by recombinant rat fatty-acid amide hydrolase. Biochem Biophys Res Commun 237(3):512–515

    Article  PubMed  CAS  Google Scholar 

  • Lambert DM, Vandevoorde S, Jonsson KO, Fowler CJ (2002) The palmitoylethanolamide family: a new class of anti-inflammatory agents? Curr Med Chem 9(6):663–674

    Article  PubMed  CAS  Google Scholar 

  • Lauckner JE, Jensen JB, Chen H-Y, Lu H-C, Hille B, Mackie K (2008) GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci U S A 105:2699–2704

    Article  PubMed  CAS  Google Scholar 

  • Liu J, Wang L, Harvey-White J, Osei-Hyiaman D, Razdan R, Gong Q, Chan AC, Zhou Z, Huang BX, Kim HY, Kunos G (2006) A biosynthetic pathway for anandamide. Proc Natl Acad Sci U S A 103(36):13345–13350

    Article  PubMed  CAS  Google Scholar 

  • Liu DZ, Hu CM, Huang CH, Wey SP, Jan TR (2010) Cannabidiol attenuates delayed-type hypersensitivity reactions via suppressing T-cell and macrophage reactivity. Acta Pharmacol Sin 31:1611–1617

    Article  PubMed  CAS  Google Scholar 

  • Lo Verme J, Fu J, Astarita G, La Rana G, Russo R, Calignano A, Piomelli D (2005a) The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Mol Pharmacol 67(1):15–19

    Article  PubMed  CAS  Google Scholar 

  • Lo Verme J, Gaetani S, Fu J, Oveisi F, Burton K, Piomelli D (2005b) Regulation of food intake by oleoylethanolamide. Cell Mol Life Sci 62(6):708–716

    Article  PubMed  CAS  Google Scholar 

  • Maccarrone M, Attina M, Cartoni A, Bari M, Finazzi-Agro A (2001) Gas chromatography–mass spectrometry analysis of endogenous cannabinoids in healthy and tumoral human brain and human cells in culture. J Neurochem 76(2):594–601

    Article  PubMed  CAS  Google Scholar 

  • Mackie K, Stella N (2006) Cannabinoid receptors and endocannabinoids: evidence for new players. AAPS J 8:E298–E306

    PubMed  Google Scholar 

  • Marrs WR, Blankman JL, Horne EA, Thomazeau A, Lin YH, Coy J, Bodor AL, Muccioli GG, Hu SS, Woodruff G, Fung S, Lafourcade M, Alexander JP, Long JZ, Li W, Xu C, Möller T, Mackie K, Manzoni OJ, Cravatt BF, Stella N (2010) The serine hydrolase ABHD6 controls the ­accumulation and efficacy of 2-AG at cannabinoid receptors. Nat Neurosci 13(8):951–957

    Article  PubMed  CAS  Google Scholar 

  • McCue JM, Driscoll WJ, Mueller GP (2008) Cytochrome c catalyzes the in vitro synthesis of arachidonoyl glycine. Biochem Biophys Res Commun 365(2):322–327

    Article  PubMed  CAS  Google Scholar 

  • McHugh D, Hu SSJ, Rimmerman N, Juknat A, Vogel Z, Walker JM, Bradshaw HB (2010) N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor. BMC Neurosci 11:44

    Article  PubMed  CAS  Google Scholar 

  • McHugh D, Page J, Dunn E, Bradshaw HB (2012) Delta(9) -THC and N-arachidonyl glycine are full agonists at GPR18 and cause migration in the human endometrial cell line, HEC-1B. Br J Pharmacol 165(8):2414–2424. doi:10.1111/j.1476-5381.2011.01497.x

    Article  PubMed  CAS  Google Scholar 

  • Mechoulam R (1986) The pharmacohistory of Cannabis sativa. In: Mechoulam R (ed) Cannabinoids as therapeutic agents. CRC Press, Boca Raton, pp 1–19

    Google Scholar 

  • Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, Pertwee RG, Griffin G, Bayewitch M, Barg J, Vogel Z (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90

    Article  PubMed  CAS  Google Scholar 

  • Mechoulam R, Parker LA, Gallily R (2002) Cannabidiol: an overview of some pharmacological aspects. J Clin Pharmacol 42:11S–19S

    PubMed  CAS  Google Scholar 

  • Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO (2007) Cannabidiol-recent advances. Chem Biodivers 4:1678–1692

    Article  PubMed  CAS  Google Scholar 

  • Merkler DJ, Merkler KA, Stern W, Fleming FF (1996) Fatty acid amide biosynthesis: a possible new role for peptidylglycine alpha-amidating enzyme and acyl-coenzyme A: glycine N-acyltransferase. Arch Biochem Biophys 330(2):430–434

    Article  PubMed  CAS  Google Scholar 

  • Moesgaard B, Jaroszewski JW, Hansen HS (1999) Accumulation of N-acyl-ethanolamine phospholipids in rat brains during post-decapitative ischemia: a 31p NMR study. J Lipid Res 40(3):515–521

    PubMed  CAS  Google Scholar 

  • Morishita J, Okamoto Y, Tsuboi K, Ueno M, Sakamoto H, Maekawa N, Ueda N (2005) Regional distribution and age-dependent expression of N-acylphosphatidylethanolamine-hydrolyzing phospholipase D in rat brain. J Neurochem 94(3):753–762

    Article  PubMed  CAS  Google Scholar 

  • Muccioli GG, Stella N (2008) Microglia produce and hydrolyze palmitoylethanolamide. Neuropharmacology 54(1):16–22

    Article  PubMed  CAS  Google Scholar 

  • Muccioli GG, Xu C, Odah E, Cudaback E, Cisneros JA, Lambert DM, López Rodríguez ML, Bajjalieh S, Stella N (2007) Identification of a novel endocannabinoid-hydrolyzing enzyme expressed by microglial cells. J Neurosci 27(11):2883–2889

    Article  PubMed  CAS  Google Scholar 

  • Muccioli GG, Sia A, Muchowski PJ, Stella N (2009) Genetic manipulation of palmitoylethanolamide production and inactivation in Saccharomyces cerevisiae. PLoS One 4(6):e5942

    Article  PubMed  CAS  Google Scholar 

  • Mueller GP, Driscoll WJ (2007) In vitro synthesis of oleoylglycine by cytochrome c points to a novel pathway for the production of lipid signaling molecules. J Biol Chem 282(31):22364–22369

    Article  PubMed  CAS  Google Scholar 

  • Nabemoto M, Mashimo M, Someya A, Nakamura H, Hirabayashi T, Fujino H, Kaneko M, Okuma Y, Saito T, Yamaguchi N, Murayama T (2008) Release of arachidonic acid by 2-arachidonoyl glycerol and HU210 in PC12 cells; roles of Src, phospholipase C and cytosolic phospholipase A(2)alpha. Eur J Pharmacol 590(1–3):1–11

    Article  PubMed  CAS  Google Scholar 

  • Nandi DL, Lucas SV, Webster LT Jr (1979) Benzoyl-coenzyme A: glycine N-acyltransferase and phenylacetyl-coenzyme A: glycine N-acyltransferase from bovine liver mitochondria. Purification and characterization. J Biol Chem 254(15):7230–7237

    PubMed  CAS  Google Scholar 

  • Natarajan V, Schmid PC, Schmid HH (1986) N-acylethanolamine phospholipid metabolism in normal and ischemic rat brain. Biochim Biophys Acta 878(1):32–41

    Article  PubMed  CAS  Google Scholar 

  • Nevalainen T, Irving AJ (2010) GPR55, a lysophosphatidylinositol receptor with cannabinoid sensitivity? Curr Top Med Chem 10:799–813

    Article  PubMed  CAS  Google Scholar 

  • Núñez E, Benito C, Pazos MR, Barbachano A, Fajardo O, González S, Tolón RM, Romero J (2004) Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse 53:208–213

    Article  PubMed  CAS  Google Scholar 

  • O’Byrne J, Hunt MC, Rai DK, Saeki M, Alexson SE (2003) The human bile acid-CoA:amino acid N-acyltransferase functions in the conjugation of fatty acids to glycine. J Biol Chem 278(36):34237–34244

    Article  PubMed  CAS  Google Scholar 

  • O’Sullivan SE (2007) Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol 152(5):576–582

    Article  PubMed  CAS  Google Scholar 

  • Oh DY, Yoon JM, Moon MJ, Hwang JI, Choe H, Lee JY, Kim JI, Kim S, Rhim H, O’Dell DK, Walker JM, Na HS, Lee MG, Kwon HB, Kim K, Seong JY (2008) Identification of farnesyl pyrophosphate and N-arachidonylglycine as endogenous ligands for GPR92. J Biol Chem 283(30):21054–21064

    Article  PubMed  CAS  Google Scholar 

  • Oka S, Nakajima K, Yamashita A, Kishimoto S, Sugiura T (2007) Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem Biophys Res Commun 362:928–934

    Article  PubMed  CAS  Google Scholar 

  • Oka S, Kimura S, Toshida T, Ota R, Yamashita A, Sugiura T (2010) Lysophosphatidylinositol induces rapid phosphorylation of p38 mitogen-activated protein kinase and activating transcription factor 2 in HEK293 cells expressing GPR55 and IM-9 lymphoblastoid cells. J Biochem 147:671–678

    Article  PubMed  CAS  Google Scholar 

  • Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N (2004) Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem 279(7):5298–5305

    Article  PubMed  CAS  Google Scholar 

  • Overton HA, Fyfe MC, Reynet C (2008) GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity. Br J Pharmacol 153(suppl 1):S76–S81

    PubMed  CAS  Google Scholar 

  • Pacher P, Mechoulam R (2011) Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog Lipid Res 50:193–211

    Article  PubMed  CAS  Google Scholar 

  • Pertwee RG (2005) Pharmacological actions of cannabinoids. Handb Exp Pharmacol 168:1–51

    Article  PubMed  CAS  Google Scholar 

  • Pertwee RG (2008) Ligands that target cannabinoid receptors in the brain: from THC to anandamide and beyond. Addict Biol 13:147–159

    Article  PubMed  CAS  Google Scholar 

  • Pertwee RG, Ross RA (2002) Cannabinoid receptors and their ligands. Prostaglandins Leukot Essent Fatty Acids 66:101–121

    Article  PubMed  CAS  Google Scholar 

  • Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev 62:588–631

    Article  PubMed  CAS  Google Scholar 

  • Pietr M, Kozela E, Levy R, Rimmerman N, Lin YH, Stella N, Vogel Z, Juknat A (2009) Differential changes in GPR55 during microglial activation. FEBS Lett 583:2071–2076

    Article  PubMed  CAS  Google Scholar 

  • Piñeiro R, Maffucci T, Falasca M (2011) The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation. Oncogene 30:142–152

    Article  PubMed  CAS  Google Scholar 

  • Ponomarev ED, Shriver LP, Maresz K, Dittel BN (2005) Microglial cell activation and proliferation precedes the onset of CNS autoimmunity. J Neurosci Res 81(3):374–389

    Article  PubMed  CAS  Google Scholar 

  • Price TJ, Patwardhan A, Akopian AN, Hargreaves KM, Flores CM (2004) Cannabinoid receptor-independent actions of the aminoalkylindole WIN 55,212-2 on trigeminal sensory neurons. Br J Pharmacol 142:257–266

    Article  PubMed  CAS  Google Scholar 

  • Prinz M, Mildner A (2011) Microglia in the CNS: immigrants from another world. Glia 59:177–187

    Article  PubMed  Google Scholar 

  • Prinz M, Priller J, Sisodia SS, Ransohoff RM (2011) Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci 14(10):1–9

    Google Scholar 

  • Prusakiewicz JJ, Kingsley PJ, Kozak KR, Marnett LJ (2002) Selective oxygenation of N-arachidonylglycine by cyclooxygenase-2. Biochem Biophys Res Commun 296(3):612–617

    Article  PubMed  CAS  Google Scholar 

  • Puffenbarger RA, Boothe C, Cabral GA (2000) Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells. Glia 29:58–69

    Article  PubMed  CAS  Google Scholar 

  • Qin Y, Verdegaal EM, Siderius M, Bebelman JP, Smit MJ, Leurs R, Willemze R, Tensen CP, Osanto S (2011) Quantitative expression profiling of G-protein-coupled receptors (GPCRs) in metastatic melanoma: the constitutively active orphan GPCR GPR18 as novel drug target. Pigment Cell Melanoma Res 24(1):207–218

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Rakhshan F, Day TA, Blakely RD, Barker EL (2000) Carrier-mediated uptake of the endogenous cannabinoid anandamide in RBL-2H3 cells. J Pharmacol Exp Ther 292(3):960–967

    PubMed  CAS  Google Scholar 

  • Rimmerman N, Bradshaw HB, Hughes HV, Chen JCS, Hu SSJ, McHugh D, Vefring D, Jahnsen JA, Thompson EL, Masuda K, Cravatt BF, Burstein S, Vasko MR, Prieto AL, Walker JM (2008) N-palmitoyl glycine a novel endogenous lipid acts as a modulator of calcium influx and nitric oxide production in sensory pathways. Mol Pharm 74:213–224

    Article  CAS  Google Scholar 

  • Rimmerman N, Bradshaw HB, Kozela E, Levy R, Juknat A, Vogel Z (2012) Compartmentalization of endocannabinoids into lipid rafts in a microglial cell line devoid of caveolin-1. Br J Pharmacol 165:2436–2449

    Article  CAS  Google Scholar 

  • Rimmerman N, Juknat A, Kozela E, Levy R, Bradshaw HB, Vogel Z (2011) The non-psychoactive plant cannabinoid, cannabidiol affects cholesterol metabolism-related genes in microglial cells. Cell Mol Neurobiol 31:921–930

    Article  PubMed  CAS  Google Scholar 

  • Romero-Sandoval EA, Horvath R, Landry RP, DeLeo JA (2009) Cannabinoid receptor type 2 activation induces a microglial anti-inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation. Mol Pain 5:25

    Article  PubMed  CAS  Google Scholar 

  • Rosenkilde MM, Benned-Jensen T, Andersen H, Holst PJ, Kledal TN, Luttichau HR, Larsen JK, Christensen JP, Schwartz TW (2006) Molecular pharmacological phenotyping of EBI2. An orphan seven-transmembrane receptor with constitutive activity. J Biol Chem 281(19):13199–13208

    Article  PubMed  CAS  Google Scholar 

  • Ross RA (2008) The enigmatic pharmacology of GPR55. Trends Pharmacol Sci 30:156–163

    Article  CAS  Google Scholar 

  • Ross RA (2011) L-α-Lysophosphatidylinositol meets GPR55: a deadly relationship. Trends Pharmacol Sci 32:265–269

    Article  PubMed  CAS  Google Scholar 

  • Ross HR, Gilmore AJ, Connor M (2009) Inhibition of human recombinant T-type calcium channels by the endocannabinoid N-arachidonoyl dopamine. Br J Pharmacol 156(5):740–750

    Article  PubMed  CAS  Google Scholar 

  • Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson N-O, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ (2007) The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 152:1092–1101

    Article  PubMed  CAS  Google Scholar 

  • Samuelson LC, Swanberg LJ, Gantz I (1996) Mapping of the novel G protein-coupled receptor Gpr18 to distal mouse chromosome 14. Mamm Genome 7:920–921

    Article  PubMed  CAS  Google Scholar 

  • Savinainen JR, Saario SM, Laitinen JT (2012) The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors. Acta Physiol (Oxf) 204(2):267–276

    Article  CAS  Google Scholar 

  • Sawzdargo M, Nguyen T, Lee DK, Lynch KR, Cheng R, Heng H, George SR, O’Dowd BF (1999) Identification and cloning of three novel human G protein-coupled receptor genes GPR52, GPR53 and GPR55: GPR55 is extensively expressed in human brain. Mol Brain Res 64:193–198

    Article  PubMed  CAS  Google Scholar 

  • Schachter D, Taggart JV (1954) Glycine N-acylase: purification and properties. J Biol Chem 208:263–275

    PubMed  CAS  Google Scholar 

  • Schmid HH, Berdyshev EV (2002) Cannabinoid receptor-inactive N-acylethanolamines and other fatty acid amides: metabolism and function. Prostaglandins Leukot Essent Fatty Acids 66:363–376

    Article  PubMed  CAS  Google Scholar 

  • Schmid PC, Schwartz KD, Smith CN, Krebsbach RJ, Berdyshev EV, Schmid HH (2000) A sensitive endocannabinoid assay. The simultaneous analysis of N-acylethanolamines and 2-monoacylglycerols. Chem Phys Lipids 104:185–191

    Article  PubMed  CAS  Google Scholar 

  • Scuderi C, Filippis DD, Iuvone T, Blasio A, Steardo A, Esposito G (2009) Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders. Phytother Res 23:597–602

    Article  PubMed  CAS  Google Scholar 

  • Sharir H, Abood ME (2010) Pharmacological characterization of GPR55, a putative cannabinoid receptor. Pharmacol Ther 126:301–313

    Article  PubMed  CAS  Google Scholar 

  • Sheskin T, Hanus L, Slager J, Vogel Z, Mechoulam R (1997) Structural requirements for binding of anandamide-type compounds to the brain cannabinoid receptor. J Med Chem 40(5): 659–667

    Article  PubMed  CAS  Google Scholar 

  • Soulet D, Rivest S (2008) Bone-marrow-derived microglia: myth or reality? Curr Opin Pharmacol 8:1–11

    Article  CAS  Google Scholar 

  • Stadel R, Ahn KH, Kendall DA (2011) The cannabinoid type-1 receptor carboxyl-terminus, more than just a tail. J Neurochem 117:1–18

    Article  PubMed  CAS  Google Scholar 

  • Staton PC, Hatcher JP, Walker DJ, Morrison AD, Shapland EM, Hughes JP, Chong E, Mander PK, Green P, Billinton A, Fulleylove M, Lancaster HC, Smith JC, Bailey LT, Wise A, Brown AJ, Richardson JC, Chessell IP (2008) The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic pain. Pain 139:225–236

    Article  PubMed  CAS  Google Scholar 

  • Stella N (2004) Cannabinoid signaling in glial cells. Glia 48(4):267–277

    Article  PubMed  Google Scholar 

  • Stella N (2009) Endocannabinoid signaling in microglial cells. Neuropharmacology 56:244–253

    Article  PubMed  CAS  Google Scholar 

  • Stella N (2010) Cannabinoid and cannabinoid-like receptors in microglia, astrocytes and astrocytomas. Glia 58:1017–1030

    Article  PubMed  Google Scholar 

  • Succar R, Mitchell VA, Vaughan CW (2007) Actions of N-arachidonoyl-glycine in a rat inflammatory pain model. Mol Pain 3:24

    Article  PubMed  CAS  Google Scholar 

  • Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97

    Article  PubMed  CAS  Google Scholar 

  • Sun YX, Tsuboi K, Okamoto Y, Tonai T, Murakami M, Kudo I et al (2004) Biosynthesis of anandamide and N-palmitoylethanolamine by sequential actions of phospholipase A2 and lysophospholipase D. Biochem J 380(pt 3):749–756

    Article  PubMed  CAS  Google Scholar 

  • Tham CS, Whitaker J, Luo L, Webb M (2007) Inhibition of microglial fatty acid amide hydrolase modulates LPS stimulated release of inflammatory mediators. FEBS Lett 581:2899–2904

    Article  PubMed  CAS  Google Scholar 

  • Tsuboi K, Sun YX, Okamoto Y, Araki N, Tonai T, Ueda N (2005) Molecular characterization of N-acylethanolamine-hydrolyzing acid amidase, a novel member of the choloylglycine hydrolase family with structural and functional similarity to acid ceramidase. J Biol Chem 280:11082–11092

    Article  PubMed  CAS  Google Scholar 

  • Tsuboi K, Takezaki N, Ueda N (2007) The N-acylethanolamine-hydrolyzing acid amidase (NAAA). Chem Biodivers 4:1914–1925

    Article  PubMed  CAS  Google Scholar 

  • Ueda N, Okamoto Y, Morishita J (2005) N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: a novel enzyme of the beta-lactamase fold family releasing anandamide and other N-acylethanolamines. Life Sci 77:1750–1758

    Article  PubMed  CAS  Google Scholar 

  • Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison JS, Marnett LJ, Di Marzo V, Pittman QJ, Patel KD, Sharkey KA (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptor. Science 310:329–332

    Article  PubMed  CAS  Google Scholar 

  • Vogel Z, Bayewitch M, Levy R, Matus-Leibovitch N, Hanus L, Ben-Shabat S, Mechoulam R, Avidor-Reiss T, Barg J (1994) Binding and functional studies with the peripheral and neuronal cannabinoid receptors. Regul Pept 54:313–314

    Article  CAS  Google Scholar 

  • Waldeck-Weiermair M, Zoratti C, Osibow K, Balenga N, Goessnitzer E, Waldhoer M, Malli R, Graier WF (2008) Integrin clustering enables anandamide-induced Ca2+ signaling in endothelial cells via GPR55 by protection against CB1-receptor-triggered repression. J Cell Sci 121:1704–1717

    Article  PubMed  CAS  Google Scholar 

  • Walter L, Stella N (2004) Cannabinoids and neuroinflammation. Br J Pharmacol 141:775–785

    Article  PubMed  CAS  Google Scholar 

  • Walter L, Franklin A, Witting A, Wade C, Xie Y, Kunos G, Mackie K, Stella N (2003) Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci 23:1398–1405

    PubMed  CAS  Google Scholar 

  • Waluk DP, Schultz N, Hunt MC (2010) Identification of glycine N-acyltransferase-like 2 (GLYATL2) as a transferase that produces N-acyl glycines in humans. FASEB J 24: 2795–2803

    Article  PubMed  CAS  Google Scholar 

  • Watanabe K, Kayano Y, Matsunaga T, Yamamoto I, Yoshimura H (1996) Inhibition of anandamide amidase activity in mouse brain microsomes by cannabinoids. Biol Pharm Bull 19: 1109–1111

    Article  PubMed  CAS  Google Scholar 

  • Whyte LS, Ryberg E, Sims NA, Ridge SA, Mackie K, Greasley PJ, Ross RA, Rogers MJ (2009) The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc Natl Acad Sci U S A 106:16511–16516

    Article  PubMed  CAS  Google Scholar 

  • Wiles AL, Pearlman RJ, Rosvall M, Aubrey KR, Vandenberg RJ (2006) N-Arachidonyl-glycine inhibits the glycine transporter, GLYT2a. J Neurochem 99:781–786

    Article  PubMed  CAS  Google Scholar 

  • Worzfeld T, Wettschureck N, Offermanns S (2008) G12/G13-mediated signalling in mammalian physiology and disease. Trends Pharmacol Sci 29(11):582–589

    Article  PubMed  CAS  Google Scholar 

  • Yevenes GE, Zeilhofer HU (2011a) Allosteric modulation of glycine receptors. Br J Pharmacol 164:224–236

    Article  PubMed  CAS  Google Scholar 

  • Yevenes GE, Zeilhofer HU (2011b) Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids. PLoS One 6:e23886

    Article  PubMed  CAS  Google Scholar 

  • Yin H, Chu A, Li W, Wang B, Shelton F, Otero F, Nguyen DG, Caldwell JS, Chen YA (2009) Lipid G protein-coupled receptor ligand identification using β-arrestin PathHunterTM assay. J Biol Chem 284:12328–12338

    Article  PubMed  CAS  Google Scholar 

  • Yu W, Lin Z, Hegarty JP, John G, Chen X, Faber PW, Kelly AA, Wang Y, Poritz LS, Schreiber S, Koltun WA (2010) Genes regulated by Nkx2-3 in siRNA-mediated knockdown B cells: implication of endothelin-1 in inflammatory bowel disease. Mol Genet Metab 100:88–95

    Article  PubMed  CAS  Google Scholar 

  • Zhang H, Hilton DA, Hanemann CO, Zajicek J (2011) Cannabinoid receptor and N-acyl phosphatidylethanolamine phospholipase D—evidence for altered expression in multiple sclerosis. Brain Pathol 21:544–557

    PubMed  CAS  Google Scholar 

  • Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D, Högestätt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400:452–457

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Dr. Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases, Tel Aviv University, Tel Aviv, Israel

    Neta Rimmerman, Ewa Kozela, Zvi Vogel & Ana Juknat

  2. Neurobiology Department, Weizmann Institute of Science, Rehovot, Israel

    Rivka Levy & Zvi Vogel

Authors
  1. Neta Rimmerman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ewa Kozela
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rivka Levy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zvi Vogel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ana Juknat
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zvi Vogel .

Editor information

Editors and Affiliations

  1. , Anatomy and Cell Biology, Temple University School of Medicine, 3500 N. Broad Street, Philadelphia, 19140, Pennsylvania, USA

    Mary E. Abood

  2. National Institutes of Health, Division of Basic Neuroscience and Behav, National Institute on Drug Abuse, 6001 Executive Blvd, Bethesda, 20892, Maryland, USA

    Roger G Sorensen

  3. , Pharmacology and Psychiatry and Behavior, University of Washington, Box 357280, Seattle, 98195, Washington, USA

    Nephi Stella

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Rimmerman, N., Kozela, E., Levy, R., Vogel, Z., Juknat, A. (2013). Cannabinoid Signaling Through Non-CB1R/Non-CB2R Targets in Microglia. In: Abood, M., Sorensen, R., Stella, N. (eds) endoCANNABINOIDS. The Receptors, vol 24. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4669-9_7

Download citation

Publish with us

Policies and ethics

Search

Navigation