Skip to main content

Pharmacological Actions of Cannabinoids

  • Chapter
Cannabinoids

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 168))

Abstract

Mammalian tissues express at least two types of cannabinoid receptor, CB1 and CB2, both G protein coupled. CB1 receptors are expressed predominantly at nerve terminals where they mediate inhibition of transmitter release. CB2 receptors

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 629.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 799.99
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

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Abadji V, Lin S, Taha G, Griffin G, Stevenson LA, Pertwee RG, Makriyannis A (1994) (R)-methanandamide: a chiral novel anandamide possessing higher potency and metabolic stability. J Med Chem 37:1889–1893

    Article  PubMed  CAS  Google Scholar 

  • Adams IB, Ryan W, Singer M, Thomas BF, Compton DR, Razdan RK, Martin BR (1995) Evaluation of cannabinoid receptor binding and in vivo activities for anandamide analogs. J Pharmacol Exp Ther 273:1172–1181

    PubMed  CAS  Google Scholar 

  • Ahluwalia J, Yaqoob M, Urban L, Bevan S, Nagy I (2003) Activation of capsaicin-sensitive primary sensory neurones induces anandamide production and release. J Neurochem 84:585–591

    Article  PubMed  CAS  Google Scholar 

  • Akinshola BE, Chakrabarti A, Onaivi ES (1999a) In-vitro and in-vivo action of cannabinoids. Neurochem Res 24:1233–1240

    Article  PubMed  CAS  Google Scholar 

  • Akinshola BE, Taylor RE, Ogunseitan AB, Onaivi ES (1999b) Anandamide inhibition of recombinant AMPA receptor subunits in Xenopus oocytes is increased by forskolin and 8-bromo-cyclic AMP. Naunyn Schmiedebergs Arch Pharmacol 360:242–248

    Article  PubMed  CAS  Google Scholar 

  • Al-Hayani A, Wease KN, Ross RA, Pertwee RG, Davies SN (2001) The endogenous cannabinoid anandamide activates vanilloid receptors in the rat hippocampal slice. Neuropharmacology 41:1000–1005

    Article  PubMed  CAS  Google Scholar 

  • Balster RL, Prescott WR (1992) Δ 9-Tetrahydrocannabinol discrimination in rats as a model for cannabis intoxication. Neurosci Biobehav Rev 16:55–62

    Article  PubMed  CAS  Google Scholar 

  • Barann M, Molderings G, Brüss M, Bönisch H, Urban BW, Göthert M (2002) Direct inhibition by cannabinoids of human 5-HT3A receptors: probable involvement of an allosteric modulatory site. Br J Pharmacol 137:589–596

    Article  PubMed  CAS  Google Scholar 

  • Bayewitch M, Rhee M-H, Avidor-Reiss T, Breuer A, Mechoulam R, Vogel Z (1996) (—)-Δ 9-tetrahydrocannabinol antagonizes the peripheral cannabinoid receptor-mediated inhibition of adenylyl cyclase. J Biol Chem 271:9902–9905

    PubMed  CAS  Google Scholar 

  • Begg M, Mo F-M, Offertáler L, Bátkai S, Pacher P, Razdan RK, Lovinger DM, Kunos G (2003) G protein-coupled endothelial receptor for atypical cannabinoid ligands modulates a Ca2+-dependent K+ current. J Biol Chem 278:46188–46194

    Article  PubMed  CAS  Google Scholar 

  • Ben-Shabat S, Fride E, Sheskin T, Tamiri T, Rhee M-H, Vogel Z, Bisogno T, De Petrocellis L, Di Marzo V, Mechoulam R (1998) An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol 353:23–31

    Article  PubMed  CAS  Google Scholar 

  • Berdyshev EV, Schmid PC, Krebsbach RJ, Hillard CJ, Huang CS, Chen N, Dong Z, Schmid HHO (2001) Cannabinoid-receptor-independent cell signalling by N-acylethanolamines. Biochem J 360:67–75

    Article  PubMed  CAS  Google Scholar 

  • Bisogno T, Melck D, Bobrov MY, Gretskaya NM, Bezuglov VV, De Petrocellis L, Di Marzo V (2000) N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo. Biochem J 351:817–824

    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 134:845–852

    Article  PubMed  CAS  Google Scholar 

  • Breivogel CS, Childers SR (2000) Cannabinoid agonist signal transduction in rat brain: comparison of cannabinoid agonists in receptor binding, G-protein activation, and adenylyl cyclase inhibition. J Pharmacol Exp Ther 295:328–336

    PubMed  CAS  Google Scholar 

  • Breivogel CS, Sim LJ, Childers SR (1997) Regional differences in cannabinoid receptor/G-protein coupling in rat brain. J Pharmacol Exp Ther 282:1632–1642

    PubMed  CAS  Google Scholar 

  • Breivogel CS, Selley DE, Childers SR (1998) Cannabinoid receptor agonist efficacy for stimulating [35S]GTPγS binding to rat cerebellar membranes correlates with agonist-induced decreases in GDP affinity. J Biol Chem 273:16865–16873

    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 

  • Brooks JW, Pryce G, Bisogno T, Jaggar SI, Hankey DJR, Brown P, Bridges D, Ledent C, Bifulco M, Rice ASC, Di Marzo V, Baker D (2002) 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 439:83–92

    Article  PubMed  CAS  Google Scholar 

  • Busch-Petersen J, Hill WA, Fan PS, Khanolkar A, Xie X-Q, Tius MA, Makriyannis A (1996) Unsaturated side chain β-11-hydroxyhexahydrocannabinol analogs. J Med Chem 39:3790–3796

    Article  PubMed  CAS  Google Scholar 

  • Calandra B, Portier M, Kernéis A, Delpech M, Carillon C, Le Fur G, Ferrara P, Shire D (1999) Dual intracellular signaling pathways mediated by the human cannabinoid CB1 receptor. Eur J Pharmacol 374:445–455

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Calignano A, La Rana G, Piomelli D (2001) Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide. Eur J Pharmacol 419:191–198

    Article  PubMed  CAS  Google Scholar 

  • Chaytor AT, Martin PEM, Evans WH, Randall MD, Griffith TM (1999) The endothelial component of cannabinoid-induced relaxation in rabbit mesenteric artery depends on gap junctional communication. J Physiol 520:539–550

    Article  PubMed  CAS  Google Scholar 

  • Cheer JF, Cadogan A-K, Marsden CA, Fone KCF, Kendall DA (1999) Modification of 5-HT2 receptor mediated behaviour in the rat by oleamide and the role of cannabinoid receptors. Neuropharmacology 38:533–541

    Article  PubMed  CAS  Google Scholar 

  • Chemin J, Monteil A, Perez-Reyes E, Nargeot J, Lory P (2001) Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide. EMBO J 20:7033–7040

    Article  PubMed  CAS  Google Scholar 

  • Chin C, Lucas-Lenard J, Abadji V, Kendall DA (1998) Ligand binding and modulation of cyclic AMP levels depend on the chemical nature of residue 192 of the human cannabinoid receptor 1. J Neurochem 70:366–373

    PubMed  CAS  Google Scholar 

  • Christopoulos A, Wilson K (2001) Interaction of anandamide with the M1 and M4 muscarinic acetylcholine receptors. Brain Res 915:70–78

    Article  PubMed  CAS  Google Scholar 

  • Compton DR, Aceto MD, Lowe J, Martin BR (1996) In vivo characterization of a specific cannabinoid receptor antagonist (SR141716A): inhibition of Δ 9-tetrahydrocannabinol induced responses and apparent agonist activity. J Pharmacol Exp Ther 277:586–594

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Cosenza M, Gifford AN, Gatley SJ, Pyatt B, Liu Q, Makriyannis A, Volkow ND (2000) Locomotor activity and occupancy of brain cannabinoid CB1 receptors by the antagonist/inverse agonist AM281. Synapse 38:477–482

    Article  PubMed  CAS  Google Scholar 

  • Costa B, Colleoni M (1999) SR141716A induces in rats a behavioral pattern opposite to that of CB1 receptor agonists. Acta Pharmacol Sin 20:1103–1108

    CAS  Google Scholar 

  • Craib SJ, Ellington HC, Pertwee RG, Ross RA (2001) A possible role of lipoxygenase in the activation of vanilloid receptors by anandamide in the guinea-pig bronchus. Br J Pharmacol 134:30–37

    Article  PubMed  CAS  Google Scholar 

  • Cravatt BF, Lichtman AH (2002) The enzymatic inactivation of the fatty acid amide class of signaling lipids. Chem Phys Lipids 121:135–148

    PubMed  CAS  Google Scholar 

  • Darlington CL (2003) Dexanabinol: a novel cannabinoid with neuroprotective properties. IDrugs 6:976–979

    PubMed  CAS  Google Scholar 

  • De Petrocellis L, Bisogno T, Maccarrone M, Davis JB, Finazzi-Agrò A, Di Marzo V (2001a) The activity of anandamide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabolism. J Biol Chem 276:12856–12863

    PubMed  Google Scholar 

  • De Petrocellis L, Davis JB, Di Marzo V (2001b) Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors. FEBS Lett 506:253–256

    PubMed  Google Scholar 

  • De Petrocellis L, Bisogno T, Ligresti A, Bifulco M, Melck D, Di Marzo V (2002) Effect on cancer cell proliferation of palmitoylethanolamide, a fatty acid amide interacting with both the cannabinoid and vanilloid signalling systems. Fundam Clin Pharmacol 16:297–302

    PubMed  Google Scholar 

  • De Vry J, Jentzsch KR (2002) Discriminative stimulus effects of BAY 38–7271, a novel cannabinoid receptor agonist. Eur J Pharmacol 457:147–152

    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

    PubMed  CAS  Google Scholar 

  • Devlin MG, Christopoulos A (2002) Modulation of cannabinoid agonist binding by 5-HT in the rat cerebellum. J Neurochem 80:1095–1102

    Article  PubMed  CAS  Google Scholar 

  • Di Marzo V, Melck D, Bisogno T, De Petrocellis L (1998) Endocannabinoids: endogenous cannabinoid receptor ligands with neuro modulatory action. Trends Neurosci 21:521–528

    PubMed  Google Scholar 

  • Di Marzo V, Breivogel CS, Tao Q, Bridgen DT, Razdan RK, Zimmer AM, Zimmer A, Martin BR (2000) Levels, metabolism, and pharmacological activity of anandamide in CB1 cannabinoid receptor knockout mice: evidence for non-CB1, non-CB2 receptor-mediated actions of anandamide in mouse brain. J Neurochem 75:2434–2444

    PubMed  Google Scholar 

  • Di Marzo V, Bisogno T, De Petrocellis L, Brandi I, Jefferson RG, Winckler RL, Davis JB, Dasse O, Mahadevan A, Razdan RK, Martin BR (2001) Highly selective CB1 cannabinoid receptor ligands and novel CB1/VR1 vanilloid receptor “hybrid” ligands. Biochem Biophys Res Commun 281:444–451

    PubMed  Google Scholar 

  • Di Marzo V, Griffin G, De Petrocellis L, Brandi I, Bisogno T, Williams W, Grier MC, Kulasegram S, Mahadevan A, Razdan RK, Martin BR (2002) A structure/activity relationship study on arvanil, an endocannabinoid and vanilloid hybrid. J Pharmacol Exp Ther 300:984–991

    PubMed  Google Scholar 

  • Dinh TP, Freund TF, Piomelli D (2002) A role for monoglyceride lipase in 2-arachidonoylglycerol inactivation. Chem Phys Lipids 121:149–158

    PubMed  CAS  Google Scholar 

  • Drysdale AJ, Pertwee RG, Platt B (2004) Modulation of calcium homeostasis by cannabidiol in primary hippocampal culture. Proc Br Pharmacol Soc at http://www.pa2online.org/ Vol1Issue4abst052P.html

    Google Scholar 

  • El-Remessy AB, Khalil IE, Matragoon S, Abou-Mohamed G, Tsai N-J, Roon P, Caldwell RB, Caldwell RW, Green K, Liou GI (2003) Neuroprotective effect of (-)Δ 9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. Am J Pathol 163:1997–2008

    PubMed  CAS  Google Scholar 

  • Ellington HC, Cotter MA, Cameron NE, Ross RA (2002) The effect of cannabinoids on capsaicin-evoked calcitonin gene-related peptide (CGRP) release from the isolated paw skin of diabetic and non-diabetic rats. Neuropharmacology 42:966–975

    Article  PubMed  CAS  Google Scholar 

  • ElSohly MA (2002) Chemical constituents of cannabis. In: Grotenhermen F, Russo E (eds) Cannabis and Cannabinoids Pharmacology, Toxicology and Therapeutic Potential. Haworth Press, New York, pp 27–36

    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 

  • Fan P (1995) Cannabinoid agonists inhibit the activation of 5-HT3 receptors in rat nodose ganglion neurons. J Neurophysiol 73:907–910

    PubMed  CAS  Google Scholar 

  • Fan S-F, Yazulla S (2003) Biphasic modulation of voltage-dependent currents of retinal cones by cannabinoid CBI receptor agonist WIN 55212-2. Visual Neurosci 20:177–188

    Google Scholar 

  • Farquhar-Smith WP, Rice ASC (2001) Administration of endocannabinoids prevents a referred hyperalgesia associated with inflammation of the urinary bladder. Anesthesiology 94:507–513

    PubMed  CAS  Google Scholar 

  • Farquhar-Smith WP, Jaggar SI, Rice ASC (2002) Attenuation of nerve growth factor-induced visceral hyperalgesia via cannabinoid CB1 and CB2-like receptors. Pain 97:11–21

    Article  PubMed  CAS  Google Scholar 

  • Felder CC, Briley EM, Axelrod J, Simpson JT, Mackie K, Devane WA (1993) Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction. Proc Natl Acad Sci USA 90:7656–7660

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Felder CC, Joyce KE, Briley EM, Glass M, Mackie KP, Fahey KJ, Cullinan GJ, Hunden DC, Johnson DW, Chaney MO, Koppel GA, Brownstein M (1998) LY320135, a novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation. J Pharmacol Exp Ther 284:291–297

    PubMed  CAS  Google Scholar 

  • Ferraro L, Tomasini MC, Gessa GL, Bebe BW, Tanganelli S, Antonelli T (2001) The cannabinoid receptor agonist WIN 55,212-2 regulates glutamate transmission in rat cerebral cortex: an in vivo and in vitro study. Cerebral Cortex 11:728–733

    Article  PubMed  CAS  Google Scholar 

  • Fezza F, Bisogno T, Minassi A, Appendino G, Mechoulam R, Di Marzo V (2002) Noladin ether, a putative novel endocannabinoid: inactivation mechanisms and a sensitive method for its quantification in rat tissues. FEBS Lett 513:294–298

    Article  PubMed  CAS  Google Scholar 

  • Fowler CJ (2003) Plant-derived, synthetic and endogenous cannabinoids as neuroprotective agents: non-psychoactive cannabinoids,’ entourage’ compounds and inhibitors of N-acyl ethanolamine breakdown as therapeutic strategies to avoid psychotropic effects. Brain Res Rev 41:26–43

    Article  PubMed  CAS  Google Scholar 

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

    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 23:7767–7775

    PubMed  CAS  Google Scholar 

  • Fride E, Foox A, Rosenberg E, Faigenboim M, Cohen V, Barda L, Blau H, Mechoulam R (2003) Milk intake and survival in newborn cannabinoid CB1 receptor knockout mice: evidence for a “CB3” receptor. Eur J Pharmacol 461:27–34

    Article  PubMed  CAS  Google Scholar 

  • Gallant M, Dufresne C, Gareau Y, Guay D, Leblanc Y, Prasit P, Rochette C, Sawyer N, Slipetz DM, Tremblay N, Metters KM, Labelle M (1996) New class of potent ligands for the human peripheral cannabinoid receptor. Bioorg Med Chem Lett 6:2263–2268

    Article  CAS  Google Scholar 

  • Gallily R, Even-Chen T, Katzavian G, Lehmann D, Dagan A, Mechoulam R (2003) γ-Irradiation enhances apoptosis induced by cannabidiol, a non-psychotropic cannabinoid, in cultured HL-60 myeloblastic leukemia cells. Leuk Lymphoma 44:1767–1773

    Article  PubMed  CAS  Google Scholar 

  • Gareau Y, Dufresne C, Gallant M, Rochette C, Sawyer N, Slipetz DM, Tremblay N, Weech PK, Metters KM, Labelle M (1996) Structure activity relationships of tetrahydrocannabinol analogues on human cannabinoid receptors. Bioorg Med Chem Lett 6:189–194

    Article  CAS  Google Scholar 

  • Gatley SJ, Lan R, Volkow ND, Pappas N, King P, Wong CT, Gifford AN, Pyatt B, Dewey SL, Makriyannis A (1998) Imaging the brain marijuana receptor: development of a radioligand that binds to cannabinoid CB1 receptors in vivo. J Neurochem 70:417–423

    PubMed  CAS  Google Scholar 

  • Géerard CM, Mollereau C, Vassart G, Parmentier M (1991) Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem J 279:129–134

    CAS  Google Scholar 

  • Gifford AN, Tang Y, Gatley SJ, Volkow ND, Lan R, Makriyannis A (1997) Effect of the cannabinoid receptor SPECT agent, AM 281, on hippocampal acetylcholine release from rat brain slices. Neurosci Lett 238:84–86

    Article  PubMed  CAS  Google Scholar 

  • Gifford AN, Makriyannis A, Volkow ND, Gatley SJ (2002) In vivo imaging of the brain cannabinoid receptor. Chem Phys Lipids 121:65–72

    PubMed  CAS  Google Scholar 

  • Glass M, Felder CC (1997) Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J Neurosci 17:5327–5333

    PubMed  CAS  Google Scholar 

  • Godlewski G, Göthert M, Malinowska B (2003) Cannabinoid receptor-independent inhibition by cannabinoid agonists of the peripheral 5-HT3 receptor-mediated von Bezold-Jarisch reflex. Br J Pharmacol 138:767–774

    Article  PubMed  CAS  Google Scholar 

  • Gonsiorek W, Lunn C, Fan X, Narula S, Lundell D, Hipkin RW (2000) Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: antagonism by anandamide. Mol Pharmacol 57:1045–1050

    PubMed  CAS  Google Scholar 

  • Göthert M, Brüss M, Bönisch H, Molderings GJ (1999) Presynaptic imidazoline receptors: new developments in characterization and classification. Ann N Y Acad Sci 881:171–184

    PubMed  Google Scholar 

  • Goutopoulos A, Fan P, Khanolkar AD, Xie X-Q, Lin S, Makriyannis A (2001) Stereochemical selectivity of methanandamides for the CB1 and CB2 cannabinoid receptors and their metabolic stability. Bioorg Med Chem 9:1673–1684

    PubMed  CAS  Google Scholar 

  • Griffin G, Fernando SR, Ross RA, McKay NG, Ashford MLJ, Shire D, Huffman JW, Yu S, Lainton JAH, Pertwee RG (1997) Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals. Eur J Pharmacol 339:53–61

    Article  PubMed  CAS  Google Scholar 

  • Griffin G, Tao Q, Abood ME (2000) Cloning and pharmacological characterization of the rat CB2 cannabinoid receptor. J Pharmacol Exp Ther 292:886–894

    PubMed  CAS  Google Scholar 

  • Hájos N, Freund TF (2002a) Pharmacological separation of cannabinoid sensitive receptors on hippocampal excitatory and inhibitory fibers. Neuropharmacology 43:503–510

    PubMed  Google Scholar 

  • Hájos N, Freund TF (2002b) Distinct cannabinoid sensitive receptors regulate hippocampal excitation and inhibition. Chem Phys Lipids 121:73–82

    PubMed  Google Scholar 

  • Hájos N, Katona I, Naiem SS, Mackie K, Ledent C, Mody I, Freund TF (2000) Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. Eur J Neurosci 12:3239–3249

    PubMed  Google Scholar 

  • Hájos N, Ledent C, Freund TF (2001) Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience 106:1–4

    PubMed  Google Scholar 

  • Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (—)Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95:8268–8273

    Article  PubMed  CAS  Google Scholar 

  • Hampson AJ, Grimaldi M, Lolic M, Wink D, Rosenthal R, Axelrod J (2000) Neuroprotective antioxidants from marijuana. Ann N Y Acad Sci 899:274–282

    PubMed  CAS  Google Scholar 

  • Hanus L, Breuer A, Tchilibon S, Shiloah S, Goldenberg D, Horowitz M, Pertwee RG, Ross RA, Mechoulam R, Fride E (1999) HU-308: a specific agonist for CB2, a peripheral cannabinoid receptor. Proc Natl Acad Sci USA 96:14228–14233

    Article  PubMed  CAS  Google Scholar 

  • Hanus L, Abu-Lafi S, Fride E, Breuer A, Vogel Z, Shalev DE, Kustanovich I, Mechoulam R (2001) 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc Natl Acad Sci USA 98:3662–3665

    Article  PubMed  CAS  Google Scholar 

  • Helyes Z, Németh J, Thán M, Bölcskei K, Pintér E, Szolcsányi J (2003) Inhibitory effect of anandamide on resiniferatoxin-induced sensory neuropeptide release in vivo and neuropathic hyperalgesia in the rat. Life Sci 73:2345–2353

    Article  PubMed  CAS  Google Scholar 

  • Hermann H, De Petrocellis L, Bisogno T, Schiano Moriello A, Lutz B, Di Marzo V (2003) Dual effect of cannabinoid CB1 receptor stimulation on a vanilloid VR1 receptor-mediated response. Cell Mol Life Sci 60:607–616

    PubMed  CAS  Google Scholar 

  • Hillard CJ (2000) Biochemistry and pharmacology of the endocannabinoids arachidonylethanolamide and 2-arachidonylglycerol. Prostaglandins Other Lipid Mediat 61:3–18

    PubMed  CAS  Google Scholar 

  • Hillard CJ, Jarrahian A (2003) Cellular accumulation of anandamide: consensus and controversy. Br J Pharmacol 140:802–808

    Article  PubMed  CAS  Google Scholar 

  • Hillard CJ, Manna S, Greenberg MJ, Dicamelli R, Ross RA, Stevenson LA, Murphy V, Pertwee RG, Campbell WB (1999) Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). J Pharmacol Exp Ther 289:1427–1433

    PubMed  CAS  Google Scholar 

  • Hirst RA, Almond SL, Lambert DG (1996) Characterisation of the rat cerebella CB1 receptor using SR141716A, a central cannabinoid receptor antagonist. Neurosci Lett 220:101–104

    Article  PubMed  CAS  Google Scholar 

  • Ho W-SV, Hiley CR (2003) Vasodilator actions of abnormal-cannabidiol in rat isolated small mesenteric artery. Br J Pharmacol 138:1320–1332

    PubMed  CAS  Google Scholar 

  • Howlett AC (1987) Cannabinoid inhibition of adenylate cyclase: relative activity of constituents and metabolites of marihuana. Neuropharmacology 26:507–512

    Article  PubMed  CAS  Google Scholar 

  • Howlett AC, Fleming RM (1984) Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. Mol Pharmacol 26:532–538

    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 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Huffman JW, Liddle J, Yu S, Aung MM, Abood ME, Wiley JL, Martin BR (1999) 3-(1’,1’-dimethylbutyl)-1-deoxy-Δ8-THC and related compounds: synthesis of selective ligands for the CB2 receptor. Bioorg Med Chem 7:2905–2914

    PubMed  CAS  Google Scholar 

  • Huffman JW, Bushell SM, Miller JRA, Wiley JL, Martin BR (2002) 1-methoxy-, 1-deoxy-11-hydroxy-and 11-hydroxy-1-methoxy-Δ8-tetrahydrocannabinols: new selective ligands for the CB2 receptor. Bioorg Med Chem 10:4119–4129

    PubMed  CAS  Google Scholar 

  • Hurst DP, Lynch DL, Barnett-Norris J, Hyatt SM, Seltzman HH, Zhong M, Song Z-H, Nie J, Lewis D, Reggio PH (2002) N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) interaction with LYS 3.28(192) is crucial for its inverse agonism at the cannabinoid CB1 receptor. Mol Pharmacol 62:1274–1287

    Article  PubMed  CAS  Google Scholar 

  • Ibrahim MM, Deng H, Zvonok A, Cockayne DA, Kwan J, Mata HP, Vanderah TW, Lai J, Porreca F, Makriyannis A, Malan TP (2003) 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 100:10529–10533

    Article  PubMed  CAS  Google Scholar 

  • Iversen L (2003) Cannabis and the brain. Brain 126:1252–1270

    Article  PubMed  Google Scholar 

  • Iwamura H, Suzuki H, Ueda Y, Kaya T, Inaba T (2001) In vitro and in vivo pharmacological characterization of JTE-907, a novel selective ligand for cannabinoid CB2 receptor. J Pharmacol Exp Ther 296:420–425

    PubMed  CAS  Google Scholar 

  • Izzo AA, Mascolo N, Tonini M, Capasso F (2000) Modulation of peristalsis by cannabinoid CB1 ligands in the isolated guinea-pig ileum. Br J Pharmacol 129:984–990

    PubMed  CAS  Google Scholar 

  • Járai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, Zimmer AM, Bonner TI, Buckley NE, Mezey E, Razdan RK, Zimmer A, Kunos G (1999) Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci USA 96:14136–14141

    PubMed  Google Scholar 

  • Jarrahian A, Manna S, Edgemond WS, Campbell WB, Hillard CJ (2000) Structure-activity relationships among N-arachidonylethanolamine (anandamide) head group analogues for the anandamide transporter. J Neurochem 74:2597–2606

    Article  PubMed  CAS  Google Scholar 

  • Jarrahian A, Watts VJ, Barker EL (2004) D2 dopamine receptors modulate Gα-subunit coupling of the CB1 cannabinoid receptor. J Pharmacol Exp Ther 308:880–886

    PubMed  CAS  Google Scholar 

  • Jennings EA, Vaughan CW, Roberts LA, Christie MJ (2003) The actions of anandamide on rat superficial medullary dorsal horn neurons in vitro. J Physiol 548:121–129

    Article  PubMed  CAS  Google Scholar 

  • Jordt S-E, Bautista DM, Chuang H, McKemy DD, Zygmunt PM, Högestätt ED, Meng ID, Julius D (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427:260–265

    Article  PubMed  CAS  Google Scholar 

  • Kelley BG, Thayer SA (2004) Δ9-tetrahydrocannabinol antagonizes endocannabinoid modulation of synaptic transmission between hippocampal neurons in culture. Neuropharmacology 46:709–715

    Article  PubMed  CAS  Google Scholar 

  • Kenny LC, Baker PN, Kendall DA, Randall MD, Dunn WR (2002) The role of gap junctions in mediating endothelium-dependent responses to bradykinin in myometrial small arteries isolated from pregnant women. Br J Pharmacol 136:1085–1088

    Article  PubMed  CAS  Google Scholar 

  • Khanolkar AD, Abadji V, Linz S, Hill WAG, Taha G, Abouzid K, Meng Z, Fan P, Makriyannis A (1996) Head group analogs of arachidonylethanolamide, the endogenous cannabinoid ligand. J Med Chem 39:4515–4519

    Article  PubMed  CAS  Google Scholar 

  • Köfalvi A, Vizi ES, Ledent C, Sperlágh B (2003) Cannabinoids inhibit the release of [3H]glutmate from rodent hippocampal synaptosomes via a novel CB1 receptor-independent action. Eur J Neurosci 18:1973–1978

    PubMed  Google Scholar 

  • Kojima S, Sugiura T, Waku K, Kamikawa Y (2002) Contractile response to a cannabimimetic eicosanoid, 2-arachidonoylglycerol, of longitudinal smooth muscle from the guinea-pig distal colon in vitro. Eur J Pharmacol 444:203–207

    Article  PubMed  CAS  Google Scholar 

  • Krishnamurthy M, Ferreira AM, Moore BM (2003) Synthesis and testing of novel phenyl substituted side-chain analogues of classical cannabinoids. Bioorg Med Chem Lett 13:3487–3490

    Article  PubMed  CAS  Google Scholar 

  • Lambert DM, Di Paolo FG, Sonveaux P, Kanyonyo M, Govaerts SJ, Hermans E, Bueb J-L, Delzenne NM, Tschirhart EJ (1999) Analogues and homologues of N-palmitoylethanolamide, a putative endogenous CB2 cannabinoid, as potential ligands for the cannabinoid receptors. Biochim Biophys Acta 1440:266–274

    PubMed  CAS  Google Scholar 

  • Lan R, Gatley J, Lu Q, Fan P, Fernando SR, Volkow ND, Pertwee R, Makriyannis A (1999a) Design and synthesis of the CB1 selective cannabinoid antagonist AM281: a potential human SPECT ligand. AAPS PharmSci 1:U13–U24

    Article  Google Scholar 

  • Lan R, Liu Q, Fan P, Lin S, Fernando SR, McCallion D, Pertwee R, Makriyannis A (1999b) Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists. J Med Chem 42:769–776

    Article  PubMed  CAS  Google Scholar 

  • Landsman RS, Makriyannis A, Deng H, Consroe P, Roeske WR, Yamamura HI (1998) AM630 is an inverse agonist at the human cannabinoid CB1 receptor. Life Sci 62:PL109–113

    Article  Google Scholar 

  • Ledent C, Valverde O, Cossu G, Petitet F, Aubert J-F, Beslot F, Böhme GA, Imperato A, Pedrazzini T, Roques BP, Vassart G, Fratta W, Parmentier M (1999) Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283:401–404

    Article  PubMed  CAS  Google Scholar 

  • Lin S, Khanolkar AD, Fan P, Goutopoulos A, Qin C, Papahadjis D, Makriyannis A (1998) Novel analogues of arachidonylethanolamide (anandamide): affinities for the CB1 and CB2 cannabinoid receptors and metabolic stability. J Med Chem 41:5353–5361

    Article  PubMed  CAS  Google Scholar 

  • Maccarrone M, Cartoni A, Parolaro D, Margonelli A, Massi P, Bari M, Battista N, Finazzi-Agrò A (2002) Cannabimimetic activity, binding, and degradation of stearoylethanolamide within the mouse central nervous system. Mol Cell Neurosci 21:126–140

    Article  PubMed  CAS  Google Scholar 

  • Maccarrone M, Bari M, Del Principe D, Finazzi-Agrò A (2003) Activation of human platelets by 2-arachidonoylglycerol is enhanced by serotonin. Thromb Haemost 89:340–347

    PubMed  CAS  Google Scholar 

  • Mackie K, Devane WA, Hille B (1993) Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N18 neuroblastoma cells. Mol Pharmacol 44:498–503

    PubMed  CAS  Google Scholar 

  • MacLennan SJ, Reynen PH, Kwan J, Bonhaus DW (1998) Evidence for inverse agonism of SR141716A at human recombinant cannabinoid CB1 and CB2 receptors. Br J Pharmacol 124:619–622

    Article  PubMed  CAS  Google Scholar 

  • Maneuf YP, Brotchie JM (1997) Paradoxical action of the cannabinoid WIN 55,212-2 in stimulated and basal cyclic AMP accumulation in rat globus pallidus slices. Br J Pharmacol 120:1397–1398

    PubMed  CAS  Google Scholar 

  • Mang CF, Erbelding D, Kilbinger H (2001) Differential effects of anandamide on acetylcholine release in the guinea-pig ileum mediated via vanilloid and non-CB1 cannabinoid receptors. Br J Pharmacol 134:161–167

    Article  PubMed  CAS  Google Scholar 

  • Marinelli S, Vaughan CW, Christie MJ, Connor M (2002) Capsaicin activation of glutamatergic synaptic transmission in the rat locus coeruleus in vitro. J Physiol 543:531–540

    Article  PubMed  CAS  Google Scholar 

  • Marinelli S, Di Marzo V, Berretta N, Matias I, Maccarrone M, Bernardi G, Mercuri NB (2003) Presynaptic facilitation of glutamatergic synapses to dopaminergic neurons of the rat substantia nigra by endogenous stimulation of vanilloid receptors. J Neurosci 23:3136–3144

    PubMed  CAS  Google Scholar 

  • Marsicano G, Moosmann B, Hermann H, Lutz B, Behl C (2002) Neuroprotective properties of cannabinoids against oxidative stress: role of the cannabinoid receptor CB1. J Neurochem 80:448–456

    Article  PubMed  CAS  Google Scholar 

  • Martin B, Stevenson LA, Pertwee RG, Breivogel CS, Williams W, Mahadevan A, Razdan RK (2002) Agonists and silent antagonists in a series of cannabinoid sulfonamides. Symposium on the Cannabinoids. Burlington, Vermont, International Cannabinoid Research Society, p 2

    Google Scholar 

  • Martin BR, Thomas BF, Razdan RK (1995) Structural requirements for cannabinoid receptor probes. In: Pertwee RG (ed) Cannabinoid receptors. Academic Press, London, pp 35–85

    Google Scholar 

  • Massi P, Vaccani A, Ceruti S, Colombo A, Abbracchio MP, Parolaro D (2004) Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J Pharmacol Exp Ther 308:838–845

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Mauler F, Mittendorf J, Horváth E, De Vry J (2002) Characterization of the diarylether sulfonylester (—)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate (BAY 38–7271) as a potent cannabinoid receptor agonist with neuroprotective properties. J Pharmacol Exp Ther 302:359–368

    Article  PubMed  CAS  Google Scholar 

  • Mauler F, Hinz V, Augstein K-H, Fassbender M, Horváth E (2003) Neuroprotective and brain edema-reducing efficacy of the novel cannabinoid receptor agonist BAY 38-7271. Brain Res 989:99–111

    Article  PubMed  CAS  Google Scholar 

  • Mechoulam R, Gaoni Y (1967) Recent advances in the chemistry of hashish. Fortschr Chem Org Naturst 25:175–213

    PubMed  CAS  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, Fride E, Di Marzo V (1998) Endocannabinoids. Eur J Pharmacol 359:1–18

    Article  PubMed  CAS  Google Scholar 

  • Mechoulam R, Panikashvili D, Shohami E (2002) Cannabinoids and brain injury: therapeutic implications. Trends Mol Med 8:58–61

    Article  PubMed  CAS  Google Scholar 

  • Millns PJ, Chapman V, Kendall DA (2001) Cannabinoid inhibition of the capsaicin-induced calcium response in rat dorsal root ganglion neurones. Br J Pharmacol 132:969–971

    Article  PubMed  CAS  Google Scholar 

  • Misner DL, Sullivan JM (1999) Mechanism of cannabinoid effects on long-term potentiation and depression in hippocampal CA1 neurons. J Neurosci 19:6795–6805

    PubMed  CAS  Google Scholar 

  • Mo FM, Offertáler L, Kunos G (2004) Atypical cannabinoid stimulates endothelial cell migration via a Gi/Go-coupled receptor distinct from CB1, CB2 or EDG-1. Eur J Pharmacol 489:21–27

    Article  PubMed  CAS  Google Scholar 

  • Molderings GJ, Göthert M (1999) Imidazoline binding sites and receptors in cardiovascular tissue. Gen Pharmacol 32:17–22

    Article  PubMed  CAS  Google Scholar 

  • Molderings GJ, Bönisch H, Hammermann R, Göthert M, Brüss M (2002) Noradrenaline release-inhibiting receptors on PC12 cells devoid of α2-and CB1 receptors: similarities to presynaptic imidazoline and edg receptors. Neurochem Int 40:157–167

    Article  PubMed  CAS  Google Scholar 

  • Monory K, Tzavara ET, Lexime J, Ledent C, Parmentier M, Borsodi A, Hanoune J (2002) Novel, not adenylyl cyclase-coupled cannabinoid binding site in cerebellum of mice. Biochem Biophys Res Commun 292:231–235

    Article  PubMed  CAS  Google Scholar 

  • Mussinu J-M, Ruiu S, Mulè AC, Pau A, Carai MAM, Loriga G, Murineddu G, Pinna GA (2003) Tricyclic pyrazoles. Part 1: synthesis and biological evaluation of novel 1,4-dihydroindeno[1,2-c]pyrazol-based ligands for CB1and CB2 cannabinoid receptors. Bioorg Med Chem 11:251–263

    PubMed  CAS  Google Scholar 

  • Németh J, Helyes Z, Thán M, Jakab B, Pintér E, Szolcsányi J (2003) Concentration-dependent dual effect of anandamide on sensory neuropeptide release from isolated rat tracheae. Neurosci Lett 336:89–92

    PubMed  Google Scholar 

  • New DC, Wong YH (2003) BML-190 and AM251 act as inverse agonists at the human cannabinoid CB2 receptor: signalling via cAMP and inositol phosphates. FEBS Lett 536:157–160

    Article  PubMed  CAS  Google Scholar 

  • Offertáler L, Mo F-M, Bátkai 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

    PubMed  Google Scholar 

  • Onaivi ES, Chakrabarti A, Gwebu ET, Chaudhuri G (1996) Neurobehavioral effects of Δ9-THC and cannabinoid (CB1) receptor gene expression in mice. Behav Brain Res 72:115–125

    Google Scholar 

  • Oz M, Zhang L, Morales M (2002) Endogenous cannabinoid, anandamide, acts as a noncompetitive inhibitor on 5-HT3 receptor-mediated responses in Xenopus oocytes. Synapse 46:150–156

    Article  PubMed  CAS  Google Scholar 

  • Pan X, Ikeda SR, Lewis DL (1998) SR 141716A acts as an inverse agonist to increase neuronal voltage-dependent Ca2+ currents by reversal of tonic CB1 cannabinoid receptor activity. Mol Pharmacol 54:1064–1072

    PubMed  CAS  Google Scholar 

  • Papahatjis DP, Nikas SP, Andreou T, Makriyannis A (2002) Novel 1’,1’-chain substituted Δ8-tetrahydrocannabinols. Bioorg Med Chem Lett 12:3583–3586

    Article  PubMed  CAS  Google Scholar 

  • Pate DW (1999) Anandamide structure-activity relationships and mechanisms of action on intraocular pressure in the normotensive rabbit model. Doctoral dissertation. Kuopio University Publications, Kuopio

    Google Scholar 

  • Paton GS, Pertwee RG, Davies SN (1998) Correlation between cannabinoid mediated effects on paired pulse depression and induction of long term potentiation in the rat hippocampal slice. Neuropharmacology 37:1123–1130

    Article  PubMed  CAS  Google Scholar 

  • Pertwee R, Griffin G, Fernando S, Li X, Hill A, Makriyannis A (1995) AM630, a competitive cannabinoid receptor antagonist. Life Sci 56:1949–1955

    Article  PubMed  CAS  Google Scholar 

  • Pertwee RG (1988) The central neuropharmacology of psychotropic cannabinoids. Pharmacol Ther 36:189–261

    Article  PubMed  CAS  Google Scholar 

  • Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74:129–180

    Article  PubMed  CAS  Google Scholar 

  • Pertwee RG (1999a) Pharmacology of cannabinoid receptor ligands. Curr Med Chem 6:635–664

    PubMed  CAS  Google Scholar 

  • Pertwee RG (1999b) Evidence for the presence of CB1 cannabinoid receptors on peripheral neurones and for the existence of neuronal non-CB1 cannabinoid receptors. Life Sci 65:597–605

    Article  PubMed  CAS  Google Scholar 

  • Pertwee RG (2000) Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development. Expert Opin Investig Drugs 9:1553–1571

    Article  PubMed  CAS  Google Scholar 

  • Pertwee RG (2001) Cannabinoid receptors and pain. Prog Neurobiol 63:569–611

    Article  PubMed  CAS  Google Scholar 

  • Pertwee RG (2003) Inverse agonism at cannabinoid receptors. In: IJzerman AP (ed) Inverse agonism. Elsevier, Amsterdam, pp 75–86

    Google Scholar 

  • Pertwee RG (2004a) Novel pharmacological targets for cannabinoids. Curr Neuropharmacol 2:9–29

    CAS  Google Scholar 

  • Pertwee RG (2004b) The pharmacology and therapeutic potential of cannabidiol. In: Di Marzo V (ed) Cannabinoids Kluwer Academic/Plenum Publishers, New York, pp 32–83

    Google Scholar 

  • Pertwee RG (2005) Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci 76:1307–1324

    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, Coutts AA, Griffin G, Fernando SR, McCallion D, Stevenson L (1996a) Presence of cannabinoid CB1 receptors on prejunctional neurones of certain isolated tissue preparations: a brief review. Med Sci Monit 2:840–848

    Google Scholar 

  • Pertwee RG, Fernando SR, Griffin G, Ryan W, Razdan RK, Compton DR, Martin BR (1996b) Agonist-antagonist characterization of 6’-cyanohex-2’-yne-Δ8-tetrahydrocannabinol in two isolated tissue preparations. Eur J Pharmacol 315:195–201

    Article  PubMed  Google Scholar 

  • Pertwee RG, Gibson TM, Stevenson LA, Ross RA, Banner WK, Saha B, Razdan RK, Martin BR (2000) O-1057, a potentwater-soluble cannabinoid receptor agonist with antinociceptive properties. Br J Pharmacol 129:1577–1584

    Article  PubMed  CAS  Google Scholar 

  • Pertwee RG, Ross RA, Craib SJ, Thomas A (2002) (—)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens. Eur J Pharmacol 456:99–106

    Article  PubMed  CAS  Google Scholar 

  • Petitet F, Marin L, Doble A (1996) Biochemical and pharmacological characterization of cannabinoid binding sites using [3H]SR141716A. Neuroreport 7:789–792

    PubMed  CAS  Google Scholar 

  • Petitet F, Jeantaud B, Capet M, Doble A (1997) Interaction of brain cannabinoid receptors with guanine nucleotide binding protein. A radioligand binding study. Biochem Pharmacol 54:1267–1270

    Article  PubMed  CAS  Google Scholar 

  • Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq MC (1998) Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of Δ9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life Sci 63:PL1–PL6

    Article  PubMed  CAS  Google Scholar 

  • Platt B, Drysdale AJ (2004) Search and rescue: identification of cannabinoid actions relevant for neuronal survival and protection. Curr Neuropharmacol 2:103–114

    CAS  Google Scholar 

  • Porter AC, Sauer J-M, Knierman MD, Becker GW, Berna MJ, Bao J, Nomikos GG, Carter P, Bymaster FP, Leese AB, Felder CC (2002) Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther 301:1020–1024

    Article  PubMed  CAS  Google Scholar 

  • Portier M, Rinaldi-Carmona M, Pecceu F, Combes T, Poinot-Chazel C, Calandra B, Barth F, Le Fur G, Casellas P (1999) SR 144528, an antagonist for the peripheral cannabinoid receptor that behaves as an inverse agonist. J Pharmacol Exp Ther 288:582–589

    PubMed  CAS  Google Scholar 

  • Rhee M-H, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, Breuer A, Mechoulam R (1997) Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylyl cyclase. J Med Chem 40:3228–3233

    Article  PubMed  CAS  Google Scholar 

  • Richardson JD, Kilo S, Hargreaves KM (1998) Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 75:111–119

    Article  PubMed  CAS  Google Scholar 

  • Rinaldi-Carmona M, Barth F, Héaulme M, Shire D, Calandra B, Congy C, Martinez S, Maruani J, Néliat G, Caput D, Ferrara P, Soubrié P, Brelière JC, Le Fur G (1994) SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 350:240–244

    Article  PubMed  CAS  Google Scholar 

  • Rinaldi-Carmona M, Calandra B, Shire D, Bouaboula M, Oustric D, Barth F, Casellas P, Ferrara P, Le Fur G (1996a) Characterization of two cloned human CB1 cannabinoid receptor isoforms. J Pharmacol Exp Ther 278:871–878

    PubMed  CAS  Google Scholar 

  • Rinaldi-Carmona M, Pialot F, Congy C, Redon E, Barth F, Bachy A, Brelière J-C, Soubrié P, Le Fur G (1996b) Characterization and distribution of binding sites for [3H]-SR141716A, a selective brain (CB1) cannabinoid receptor antagonist, in rodent brain. Life Sci 58:1239–1247

    Article  PubMed  CAS  Google Scholar 

  • Rinaldi-Carmona M, Barth F, Millan J, Derocq J-M, Casellas P, Congy C, Oustric D, Sarran M, Bouaboula M, Calandra B, Portier M, Shire D, Brelière J-C, Le Fur G (1998) SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J Pharmacol Exp Ther 284:644–650

    PubMed  CAS  Google Scholar 

  • Ross RA (2003) Anandamide and vanilloid TRPV1 receptors. Br J Pharmacol 140:790–801

    Article  PubMed  CAS  Google Scholar 

  • Ross RA, Brockie HC, Fernando SR, Saha B, Razdan RK, Pertwee RG (1998) Comparison of cannabinoid binding sites in guinea-pig forebrain and small intestine. Br J Pharmacol 125:1345–1351

    Article  PubMed  CAS  Google Scholar 

  • Ross RA, Brockie HC, Stevenson LA, Murphy VL, Templeton F, Makriyannis A, Pertwee RG (1999a) Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656 and AM630. Br J Pharmacol 126:665–672

    Article  PubMed  CAS  Google Scholar 

  • Ross RA, Gibson TM, Stevenson LA, Saha B, Crocker P, Razdan RK, Pertwee RG (1999b) Structural determinants of the partial agonist-inverse agonist properties of 6’-azidohex-2’-yne-Δ8-tetrahydrocannabinol at cannabinoid receptors. Br J Pharmacol 128:735–743

    Article  PubMed  CAS  Google Scholar 

  • Ross RA, Gibson TM, Brockie HC, Leslie M, Pashmi G, Craib SJ, Di Marzo V, Pertwee RG (2001) Structure-activity relationship for the endogenous cannabinoid, anandamide, and certain of its analogues at vanilloid receptors in transfected cells and vas deferens. Br J Pharmacol 132:631–640

    Article  PubMed  CAS  Google Scholar 

  • Rubovitch V, Gafni M, Sarne Y (2002) The cannabinoid agonist DALN positively modulates L-type voltage-dependent calcium-channels in N18TG2 neuroblastoma cells. Mol Brain Res 101:93–102

    Article  PubMed  CAS  Google Scholar 

  • Ruiu S, Pinna GA, Marchese G, Mussinu J-M, Saba P, Tambaro S, Casti P, Vargiu R, Pani L (2003) Synthesis and characterization of NESS 0327: a novel putative antagonist of the CB1 cannabinoid receptor. J Pharmacol Exp Ther 306:363–370

    Article  PubMed  CAS  Google Scholar 

  • Savinainen JR, Järvinen T, Laine K, Laitinen JT (2001) Despite substantial degradation, 2-arachidonoylglycerol is a potent full efficacy agonist mediating CB1 receptor-dependent G-protein activation in rat cerebellar membranes. Br J Pharmacol 134:664–672

    Article  PubMed  CAS  Google Scholar 

  • Savinainen JR, Saario SM, Niemi R, Järvinen T, Laitinen JT (2003) An optimized approach to study endocannabinoid signaling: evidence against constitutive activity of rat brain adenosine A1 and cannabinoid CB1 receptors. Br J Pharmacol 140:1451–1459

    Article  PubMed  CAS  Google Scholar 

  • Schlicker E, Kathmann M (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci 22:565–572

    Article  PubMed  CAS  Google Scholar 

  • Schlicker E, Redmer A, Werner A, Kathmann M (2003) Lack of CB1 receptors increases noradrenaline release in vas deferens without affecting atrial noradrenaline release or cortical acetylcholine. Br J Pharmacol 140:323–328

    Article  PubMed  CAS  Google Scholar 

  • Selley DE, Stark S, Sim LJ, Childers SR (1996) Cannabinoidreceptor stimulationof guanosine-5’-O-(3-[35S]thio)triphosphate binding in rat brain membranes. Life Sci 59:659–668

    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 40:659–667

    Article  PubMed  CAS  Google Scholar 

  • Shire D, Carillon C, Kaghad M, Calandra B, Rinaldi-Carmona M, Le Fur G, Caput D, Ferrara P (1995) An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing. J Biol Chem 270:3726–3731

    PubMed  CAS  Google Scholar 

  • Shire D, Calandra B, Rinaldi-Carmona M, Oustric D, Pessègue B, Bonnin-Cabanne O, Le Fur G, Caput D, Ferrara P (1996) Molecular cloning, expression and function of the murine CB2 peripheral cannabinoid receptor. Biochim Biophys Acta 1307:132–136

    PubMed  Google Scholar 

  • Showalter VM, Compton DR, Martin BR, Abood ME (1996) Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands. J Pharmacol Exp Ther 278:989–999

    PubMed  CAS  Google Scholar 

  • Sim LJ, Selley DE, Childers SR (1995) In vitro autoradiography of receptor-activated G proteins in rat brain by agonist-stimulated guanylyl 5’-[γ-[35S]thio]triphosphate binding. Proc Natl Acad Sci USA 92:7242–7246

    PubMed  CAS  Google Scholar 

  • Sim-Selley LJ, Brunk LK, Selley DE (2001) Inhibitory effects of SR141716A on G-protein activation in rat brain. Eur J Pharmacol 414:135–143

    Article  PubMed  CAS  Google Scholar 

  • Simoneau II, Hamza MS, Mata HP, Siegel EM, Vanderah TW, Porreca F, Makriyannis A, Malan TP (2001) The cannabinoid agonist WIN55,212-2 suppresses opioid-induced emesis in ferrets. Anesthesiology 94:882–887

    PubMed  CAS  Google Scholar 

  • Smart D, Jonsson K-O, Vandevoorde S, Lambert DM, Fowler CJ (2002) ’Entourage’ effects of N-acyl ethanolamines at human vanilloid receptors. Comparison of effects upon anandamide-induced vanilloid receptor activation and upon anandamide metabolism. Br J Pharmacol 136:452–458

    Article  PubMed  CAS  Google Scholar 

  • Song Z-H, Bonner TI (1996) A lysine residue of the cannabinoid receptor is critical for receptor recognition by several agonists but not WIN55212-2. Mol Pharmacol 49:891–896

    PubMed  CAS  Google Scholar 

  • Storr M, Gaffal E, Saur D, Schusdziarra V, Allescher HD (2002) Effect of cannabinoids on neural transmission in rat gastric fundus. Can J Physiol Pharmacol 80:67–76

    PubMed  CAS  Google Scholar 

  • Sugiura T, Kodaka T, Kondo S, Tonegawa T, Nakane S, Kishimoto S, Yamashita A, Waku K (1996) 2-Arachidonoylglycerol, a putative endogenous cannabinoid receptor ligand, induces rapid, transient elevation of intracellular free Ca2+ in neuroblastoma x glioma hybrid NG108-15 cells. Biochem Biophys Res Commun 229:58–64

    Article  PubMed  CAS  Google Scholar 

  • Sugiura T, Kodaka T, Kondo S, Nakane S, Kondo H, Waku K, Ishima Y, Watanabe K, Yamamoto I (1997) Is the cannabinoid CB1 receptor a 2-arachidonoylglycerol receptor? Structural requirements for triggering a Ca2+ transient in NG108-15 cells. J Biochem (Tokyo) 122:890–895

    PubMed  CAS  Google Scholar 

  • Sugiura T, Kondo S, Kishimoto S, Miyashita T, Nakane S, Kodaka T, Suhara Y, Takayama H, Waku K (2000) Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor: comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells. J Biol Chem 275:605–612

    Article  PubMed  CAS  Google Scholar 

  • Suhara Y, Takayama H, Nakane S, Miyashita T, Waku K, Sugiura T (2000) Synthesis and biological activities of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, and its metabolically stable ether-linked analogues. Chem Pharm Bull (Tokyo) 48:903–907

    PubMed  CAS  Google Scholar 

  • Suhara Y, Nakane S, Arai S, Takayama H, Waku K, Ishima Y, Sugiura T (2001) Synthesis and biological activities of novel structural analogues of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand. Bioorg Med Chem Lett 11:1985–1988

    Article  PubMed  CAS  Google Scholar 

  • Tao Q, Abood ME (1998) Mutation of a highly conserved aspartate residue in the second transmembrane domain of the cannabinoid receptors, CB1 and CB2, disrupts G-protein coupling. J Pharmacol Exp Ther 285:651–658

    PubMed  CAS  Google Scholar 

  • Thomas A, Ross RA, Saha B, Mahadevan A, Razdan RK, Pertwee R (2004) 6”-Azidohex-2”-yne-cannabidiol: a potential neutral, competitive cannabinoid CB1 receptor antagonist. Eur J Pharmacol 487:213–221

    Article  PubMed  CAS  Google Scholar 

  • Tognetto M, Amadesi S, Harrison S, Creminon C, Trevisani M, Carreras M, Matera M, Geppetti P, Bianchi A (2001) Anandamide excites central terminals of dorsal root ganglion neurons via vanilloid receptor-1 activation. J Neurosci 21:1104–1109

    PubMed  CAS  Google Scholar 

  • Trendelenburg AU, Cox SL, Schelb V, Klebroff W, Khairallah L, Starke K (2000) Modulation of 3H-noradrenaline release by presynaptic opioid, cannabinoid and bradykinin receptors and β-adrenoceptors in mouse tissues. Br J Pharmacol 130:321–330

    Article  PubMed  CAS  Google Scholar 

  • Ueda N (2002) Endocannabinoid hydrolases. Prostaglandins Other Lipid Mediat 68-69:521–534

    PubMed  Google Scholar 

  • van der Stelt M, Di Marzo V (2004) Metabolic fate of endocannabinoids. Curr Neuropharmacol 2:37–48

    Google Scholar 

  • van der Stelt M, Veldhuis WB, Maccarrone M, Bär PR, Nicolay K, Veldink GA, Di Marzo V, Vliegenthart JFG (2002) Acute neuronal injury, excitotoxicity, and the endocannabinoid system. Mol Neurobiol 26:317–346

    PubMed  Google Scholar 

  • Vásquez C, Navarro-Polanco RA, Huerta M, Trujillo X, Andrade F, Trujillo-Hernández B, Hernández L (2003) Effects of cannabinoids on endogenous K+ and Ca2+ currents in HEK293 cells. Can J Physiol Pharmacol 81:436–442

    PubMed  Google Scholar 

  • Wager-Miller J, Westenbroek R, Mackie K (2002) Dimerization of G protein-coupled receptors: CB1 cannabinoid receptors as an example. Chem Phys Lipids 121:83–89

    PubMed  CAS  Google Scholar 

  • Wagner JA, Varga K, Járai Z, Kunos G (1999) Mesenteric vasodilation mediated by endothelial anandamide receptors. Hypertension 33:429–434

    PubMed  CAS  Google Scholar 

  • Walker JM, Krey JF, Chu CJ, Huang SM (2002) Endocannabinoids and related fatty acid derivatives in pain modulation. Chem Phys Lipids 121:159–172

    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 

  • White R, Hiley CR (1998) The actions of the cannabinoid receptor antagonist, SR 141716A, in the rat isolated mesenteric artery. Br J Pharmacol 125:689–696

    PubMed  CAS  Google Scholar 

  • Wiley JL, Martin BR (2002) Cannabinoid pharmacology: implications for additional cannabinoid receptor subtypes. Chem Phys Lipids 121:57–63

    Article  PubMed  CAS  Google Scholar 

  • Wiley JL, Martin BR (2003) Cannabinoid pharmacological properties common to other centrally acting drugs. Eur J Pharmacol 471:185–193

    Article  PubMed  CAS  Google Scholar 

  • Wiley JL, Beletskaya ID, Ng EW, Dai Z, Crocker PJ, Mahadevan A, Razdan RK, Martin BR (2002) Resorcinol derivatives: a novel template for the development of cannabinoid CB1/CB2 and CB2-selective agonists. J Pharmacol Exp Ther 301:679–689

    Article  PubMed  CAS  Google Scholar 

  • Wrobleski ST, Chen P, Hynes J, Lin S, Norris DJ, Pandit CR, Spergel S, Wu H, Tokarski JS, Chen X, Gillooly KM, Kiener PA, McIntyre KW, Patil-Koota V, Shuster DJ, Turk LA, Yang G, Leftheris K (2003) Rational design and synthesis of an orally active indolopyridone as a novel conformationally constrained cannabinoid ligand possessing antiinflammatory properties. J Med Chem 46:2110–2116

    Article  PubMed  CAS  Google Scholar 

  • Yao L, Fan P, Jiang Z, Mailliard WS, Gordon AS, Diamond I (2003) Addicting drugs utilize a synergistic molecular mechanism in common requiring adenosine and Gi-βγ dimers. Proc Natl Acad Sci USA 100:14379–14384

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Zygmunt PM, Andersson DA, Högestätt ED (2002) Δ9-tetrahydrocannabinol and cannabinol activate capsaicin-sensitive sensory nerves via a CB1 and CB2 cannabinoid receptorindependent mechanism. J Neurosci 22:4720–4727

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Springer-Verlag

About this chapter

Cite this chapter

Pertwee, R.G. (2005). Pharmacological Actions of Cannabinoids. In: Pertwee, R.G. (eds) Cannabinoids. Handbook of Experimental Pharmacology, vol 168. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-26573-2_1

Download citation

Publish with us

Policies and ethics