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Endocannabinoids and Their Pharmacological Actions

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Book cover Endocannabinoids

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 231))

Abstract

The endocannabinoid system consists of G protein-coupled cannabinoid CB1 and CB2 receptors, of endogenous compounds known as endocannabinoids that can target these receptors, of enzymes that catalyse endocannabinoid biosynthesis and metabolism, and of processes responsible for the cellular uptake of some endocannabinoids. This review presents in vitro evidence that most or all of the following 13 compounds are probably orthosteric endocannabinoids since they have all been detected in mammalian tissues in one or more investigation, and all been found to bind to cannabinoid receptors, probably to an orthosteric site: anandamide, 2-arachidonoylglycerol, noladin ether, dihomo-γ-linolenoylethanolamide, virodhamine, oleamide, docosahexaenoylethanolamide, eicosapentaenoylethanolamide, sphingosine, docosatetraenoylethanolamide, N-arachidonoyldopamine, N-oleoyldopamine and haemopressin. In addition, this review describes in vitro findings that suggest that the first eight of these compounds can activate CB1 and sometimes also CB2 receptors and that another two of these compounds are CB1 receptor antagonists (sphingosine) or antagonists/inverse agonists (haemopressin). Evidence for the existence of at least three allosteric endocannabinoids is also presented. These endogenous compounds appear to target allosteric sites on cannabinoid receptors in vitro, either as negative allosteric modulators of the CB1 receptor (pepcan-12 and pregnenolone) or as positive allosteric modulators of this receptor (lipoxin A4) or of the CB2 receptor (pepcan-12). Also discussed are current in vitro data that indicate the extent to which some established or putative orthosteric endocannabinoids seem to target non-cannabinoid receptors and ion channels, particularly at concentrations at which they have been found to interact with CB1 or CB2 receptors.

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Abbreviations

5-HT:

5-hydroxytryptamine

CB1 :

Cannabinoid receptor type 1

CB2 :

Cannabinoid receptor type 2

CHO:

Chinese hamster ovary

GDP:

Guanosine diphosphate

GTP:

Guanosine triphosphate

HEK:

Human embryonic kidney

NMDA:

N-methyl-D-aspartate

TRP:

Transient receptor potential

TRPA1:

TRP channel of ankyrin type 1

TRPM8:

TRP channel of melastatin type 8

TRPV1:

TRP channel of vanilloid type 1

TRPV4:

TRP channel of vanilloid type 4

References

  • 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

    CAS  PubMed  Google Scholar 

  • Amorós I, Barana A, Caballero R, Gómez R, Osuna L, Lillo MP, Tamargo J, Delpón E (2010) Endocannabinoids and cannabinoid analogues block human cardiac Kv4.3 channels in a receptor-independent manner. J Mol Cell Cardiol 48:201–210

    Article  PubMed  CAS  Google Scholar 

  • Artmann A, Petersen G, Hellgren LI, Boberg J, Skonberg C, Nellemann C, Hansen SH, Hansen HS (2008) Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine. Biochim Biophys Acta 1781:200–212

    Article  CAS  PubMed  Google Scholar 

  • Barana A, Amorós I, Caballero R, Gómez R, Osuna L, Lillo MP, Blázquez C, Guzmán M, Delpón E, Tamargo J (2010) Endocannabinoids and cannabinoid analogues block cardiac hKV1.5 channels in a cannabinoid receptor-independent manner. Cardiovasc Res 85:56–67

    Article  CAS  PubMed  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 Central  CAS  PubMed  Google Scholar 

  • Barg J, Fride E, Hanus L, Levy R, Matus-Leibovitch N, Heldman E, Bayewitch M, Mechoulam R, Vogel Z (1995) Cannabinomimetic behavioral effects of and adenylate cyclase inhibition by two new endogenous anandamides. Eur J Pharmacol 287:145–152

    Article  CAS  PubMed  Google Scholar 

  • Bauer M, Chicca A, Tamborrini M, Eisen D, Lerner R, Lutz B, Poetz O, Pluschke G, Gertsch J (2012) Identification and quantification of a new family of peptide endocannabinoids (Pepcans) showing negative allosteric modulation at CB1 receptors. J Biol Chem 287:36944–36967

    Article  PubMed Central  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Bezuglov V, Bobrov M, Gretskaya N, Gonchar A, Zinchenko G, Melck D, Bisogno T, Di Marzo V, Kuklev D, Rossi J-C, Vidal J-P, Durand T (2001) Synthesis and biological evaluation of novel amides of polyunsaturated fatty acids with dopamine. Bioorg Med Chem Lett 11:447–449

    Article  CAS  PubMed  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 Central  CAS  PubMed  Google Scholar 

  • Bonhaus DW, Chang LK, Kwan J, Martin GR (1998) Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses. J Pharmacol Exp Ther 287:884–888

    CAS  PubMed  Google Scholar 

  • Boring DL, Berglund BA, Howlett AC (1996) Cerebrodiene, arachidonyl-ethanolamide, and hybrid structures: potential for interaction with brain cannabinoid receptors. Prostaglandins Leukot Essent Fatty Acids 55:207–210

    Article  CAS  PubMed  Google Scholar 

  • Bouaboula M, Hilairet S, Marchand J, Fajas L, Le Fur G, Casellas P (2005) Anandamide induced PPARγ transcriptional activation and 3T3-L1 preadipocyte differentiation. Eur J Pharmacol 517:174–181

    Article  CAS  PubMed  Google Scholar 

  • Bradshaw HB, Walker JM (2005) The expanding field of cannabimimetic and related lipid mediators. Br J Pharmacol 144:459–465

    Article  PubMed Central  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Brighton PJ, Marczylo TH, Rana S, Konje JC, Willets JM (2011) Characterization of the endocannabinoid system, CB1 receptor signalling and desensitization in human myometrium. Br J Pharmacol 164:1479–1494

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Brown I, Cascio MG, Wahle KWJ, Smoum R, Mechoulam R, Ross RA, Pertwee RG, Heys SD (2010) Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines. Carcinogenesis 31:1584–1591

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Brown I, Cascio MG, Rotondo D, Pertwee RG, Heys SD, Wahle KWJ (2013) Cannabinoids and omega-3/6 endocannabinoids as cell death and anticancer modulators. Prog Lipid Res 52:80–109

    Article  CAS  PubMed  Google Scholar 

  • Burkey TH, Quock RM, Consroe P, Ehlert FJ, Hosohata Y, Roeske WR, Yamamura HI (1997) Relative efficacies of cannabinoid CB1 receptor agonists in the mouse brain. Eur J Pharmacol 336:295–298

    Article  CAS  PubMed  Google Scholar 

  • Butt C, Alptekin A, Shippenberg T, Oz M (2008) Endogenous cannabinoid anandamide inhibits nicotinic acetylcholine receptor function in mouse thalamic synaptosomes. J Neurochem 105:1235–1243

    Article  CAS  PubMed  Google Scholar 

  • Cazade M, Nuss CE, Bidaud I, Renger JJ, Uebele VN, Lory P, Chemin J (2014) Cross-modulation and molecular interaction at the Cav3.3 protein between the endogenous lipids and the T-type calcium channel antagonist TTA-A2. Mol Pharmacol 85:218–225

    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  CAS  PubMed  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 Central  CAS  PubMed  Google Scholar 

  • Chemin J, Nargeot J, Lory P (2007) Chemical determinants involved in anandamide-induced inhibition of T-type calcium channels. J Biol Chem 282:2314–2323

    Article  CAS  PubMed  Google Scholar 

  • Childers SR, Sexton T, Roy MB (1994) Effects of anandamide on cannabinoid receptors in rat brain membranes. Biochem Pharmacol 47:711–715

    Article  CAS  PubMed  Google Scholar 

  • Chu CJ, Huang SM, De Petrocellis L, Bisogno T, Ewing SA, Miller JD, Zipkin RE, Daddario N, Appendino G, Di Marzo V, Walker JM (2003) N-oleoyldopamine, a novel endogenous capsaicin-like lipid that produces hyperalgesia. J Biol Chem 278:13633–13639

    Article  CAS  PubMed  Google Scholar 

  • Chu Z-L, Carroll C, Chen R, Alfonso J, Gutierrez V, He H, Lucman A, Xing C, Sebring K, Zhou J, Wagner B, Unett D, Jones RM, Behan DP, Leonard J (2010) N-oleoyldopamine enhances glucose homeostasis through the activation of GPR119. Mol Endocrinol 24:161–170

    Article  PubMed  CAS  Google Scholar 

  • Cravatt BF, Prospero-Garcia O, Siuzdak G, Gilula NB, Henriksen SJ, Boger DL, Lerner RA (1995) Chemical characterization of a family of brain lipids that induce sleep. Science 268:1506–1509

    Article  CAS  PubMed  Google Scholar 

  • De Petrocellis L, Bisogno T, Davis JB, Pertwee RG, Di Marzo V (2000) Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin-like activity. FEBS Lett 483:52–56

    Article  PubMed  Google Scholar 

  • De Petrocellis L, Bisogno T, Maccarrone M, Davis JB, Finazzi-Agrò A, Di Marzo V (2001) 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

    Article  PubMed  Google Scholar 

  • De Petrocellis L, Starowicz K, Moriello AS, Vivese M, Orlando P, Di Marzo V (2007) Regulation of transient receptor potential channels of melastatin type 8 (TRPM8): effect of cAMP, cannabinoid CB1 receptors and endovanilloids. Exp Cell Res 313:1911–1920

    Article  PubMed  CAS  Google Scholar 

  • De Petrocellis L, Vellani V, Schiano-Moriello A, Marini P, Magherini PC, Orlando P, Di Marzo V (2008) Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther 325:1007–1015

    Article  PubMed  CAS  Google Scholar 

  • De Petrocellis L, Moriello AS, Imperatore R, Cristino L, Starowicz K, Di Marzo V (2012) A re-evaluation of 9-HODE activity at TRPV1 channels in comparison with anandamide: enantioselectivity and effects at other TRP channels and in sensory neurons. Br J Pharmacol 167:1643–1651

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Decher N, Streit AK, Rapedius M, Netter MF, Marzian S, Ehling P, Schlichthörl G, Craan T, Renigunta V, Köhler A, Dodel RC, Navarro-Polanco RA, Preisig-Müller R, Klebe G, Budde T, Baukrowitz T, Daut J (2010) RNA editing modulates the binding of drugs and highly unsaturated fatty acids to the open pore of Kv potassium channels. EMBO J 29:2101–2113

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Devane WA, Hanuš 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  CAS  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

    Article  PubMed  Google Scholar 

  • Duan Y, Zheng J, Nicholson RA (2008) Inhibition of [3H]batrachotoxinin A-20α-benzoate binding to sodium channels and sodium channel function by endocannabinoids. Neurochem Int 52:438–446

    Article  CAS  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

    CAS  PubMed  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 U S A 90:7656–7660

    Article  PubMed Central  CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Feng Z, Alqarni MH, Yang P, Tong Q, Chowdhury A, Wang L, Xie X-Q (2014) Modeling, molecular dynamics simulation, and mutation validation for structure of cannabinoid receptor 2 based on known crystal structures of GPCRs. J Chem Inf Model 54:2483–2499

    Article  PubMed Central  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Ghosh M, Wang HB, Ai Y, Romeo E, Luyendyk JP, Peters JM, Mackman N, Dey SK, Hla T (2007) COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARδ activation. J Exp Med 204:2053–2061

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Godlewski G, Offertáler L, Osei-Hyiaman D, Mo FM, Harvey-White J, Liu J, Davis MI, Zhang L, Razdan RK, Milman G, Pacher P, Mukhopadhyay P, Lovinger DM, Kunos G (2009) The endogenous brain constituent N-arachidonoyl L-serine is an activator of large conductance Ca2+-activated K+ channels. J Pharmacol Exp Ther 328:351–361

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gomes I, Grushko JS, Golebiewska U, Hoogendoorn S, Gupta A, Heimann AS, Ferro ES, Scarlata S, Fricker LD, Devi LA (2009) Novel endogenous peptide agonists of cannabinoid receptors. FASEB J 23:3020–3029

    Article  PubMed Central  CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Hampson AJ, Bornheim LM, Scanziani M, Yost CS, Gray AT, Hansen BM, Leonoudakis DJ, Bickler PE (1998) Dual effects of anandamide on NMDA receptor-mediated responses and neurotransmission. J Neurochem 70:671–676

    Article  CAS  PubMed  Google Scholar 

  • Hanuš L, Gopher A, Almog S, Mechoulam R (1993) Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor. J Med Chem 36:3032–3034

    Article  PubMed  Google Scholar 

  • Hanuš 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 U S A 98:3662–3665

    Article  PubMed Central  PubMed  Google Scholar 

  • Heimann AS, Gomes L, Dale CS, Pagano RL, Gupta A, de Souza LL, Luchessi AD, Castro LM, Giorgi R, Rioli V, Ferro ES, Devi LA (2007) Hemopressin is an inverse agonist of CB1 cannabinoid receptors. Proc Natl Acad Sci U S A 104:20588–20593

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hejazi N, Zhou C, Oz M, Sun H, Ye JH, Zhang L (2006) Δ9-tetrahydrocannabinol and endogenous cannabinoid anandamide directly potentiate the function of glycine receptors. Mol Pharmacol 69:991–997

    CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Huang SM, Bisogno T, Trevisani M, Al-Hayani A, De Petrocellis L, Fezza F, Tognetto M, Petros TJ, Krey JF, Chu CJ, Miller JD, Davies SN, Geppetti P, Walker JM, Di Marzo V (2002) An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc Natl Acad Sci U S A 99:8400–8405

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kim H-Y, Spector AA, Xiong Z-M (2011) A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development. Prostaglandins Other Lipid Mediat 96:114–120

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kimura T, Ohta T, Watanabe K, Yoshimura H, Yamamoto I (1998) Anandamide, an endogenous cannabinoid receptor ligand, also interacts with 5-hydroxytryptamine (5-HT) receptor. Biol Pharm Bull 21:224–226

    Article  CAS  PubMed  Google Scholar 

  • Lagalwar S, Bordayo EZ, Hoffmann KL, Fawcett JR, Frey WH (1999) Anandamides inhibit binding to the muscarinic acetylcholine receptor. J Mol Neurosci 13:55–61

    Article  CAS  PubMed  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 Central  CAS  PubMed  Google Scholar 

  • Leggett JD, Aspley S, Beckett SRG, D’Antona AM, Kendall DA, Kendall DA (2004) Oleamide is a selective endogenous agonist of rat and human CB1 cannabinoid receptors. Br J Pharmacol 141:253–262

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Li Q, Ma H-J, Song S-L, Shi M, Ma H-J, Li D-P, Zhang Y (2012) Effects of anandamide on potassium channels in rat ventricular myocytes: a suppression of I to and augmentation of KATP channels. Am J Physiol Cell Physiol 302:C924–C930

    Article  CAS  PubMed  Google Scholar 

  • Lichtman AH, Hawkins EG, Griffin G, Cravatt BF (2002) Pharmacological activity of fatty acid amides is regulated, but not mediated, by fatty acid amide hydrolase in vivo. J Pharmacol Exp Ther 302:73–79

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Lozovaya N, Yatsenko N, Beketov A, Tsintsadze T, Burnashev N (2005) Glycine receptors in CNS neurons as a target for nonretrograde action of cannabinoids. J Neurosci 25:7499–7506

    Article  CAS  PubMed  Google Scholar 

  • McDonald HA, Neelands TR, Kort M, Han P, Vos MH, Faltynek CR, Moreland RB, Puttfarcken PS (2008) Characterization of A-425619 at native TRPV1 receptors: a comparison between dorsal root ganglia and trigeminal ganglia. Eur J Pharmacol 596:62–69

    Article  CAS  PubMed  Google Scholar 

  • McHugh D, Page J, Dunn E, Bradshaw HB (2012) Δ9-tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells. Br J Pharmacol 165:2414–2424

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mechoulam R, Ben-Shabat S, Hanuš 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  CAS  PubMed  Google Scholar 

  • Mechoulam R, Fride E, Hanuš L, Sheskin T, Bisogno T, Di Marzo V, Bayewitch M, Vogel Z (1997) Anandamide may mediate sleep induction. Nature 389:25–26

    Article  CAS  PubMed  Google Scholar 

  • Moreno-Galindo EG, Barrio-Echavarría GF, Vásquez JC, Decher N, Sachse FB, Tristani-Firouzi M, Sánchez-Chapula JA, Navarro-Polanco RA (2010) Molecular basis for a high-potency open-channel block of Kv1.5 channel by the endocannabinoid anandamide. Mol Pharmacol 77:751–758

    Article  CAS  PubMed  Google Scholar 

  • Oka S, Tsuchie A, Tokumura A, Muramatsu M, Suhara Y, Takayama H, Waku K, Sugiura T (2003) Ether-linked analogue of 2-arachidonoylglycerol (noladin ether) was not detected in the brains of various mammalian species. J Neurochem 85:1374–1381

    Article  CAS  PubMed  Google Scholar 

  • Oliver D, Lien C-C, Soom M, Baukrowitz T, Jonas P, Fakler B (2004) Functional conversion between A-type and delayed rectifier K+ channels by membrane lipids. Science 304:265–270

    Article  CAS  PubMed  Google Scholar 

  • Overton HA, Babbs AJ, Doel SM, Fyfe MCT, Gardner LS, Griffin G, Jackson HC, Procter MJ, Rasamison CM, Tang-Christensen M, Widdowson PS, Williams GM, Reynet C (2006) Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab 3:167–175

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Oz M, Ravindran A, Diaz-Ruiz O, Zhang L, Morales M (2003) The endogenous cannabinoid anandamide inhibits α7 nicotinic acetylcholine receptor-mediated responses in Xenopus oocytes. J Pharmacol Exp Ther 306:1003–1010

    Article  CAS  PubMed  Google Scholar 

  • Oz M, Zhang L, Ravindran A, Morales M, Lupica CR (2004) Differential effects of endogenous and synthetic cannabinoids on α7-nicotinic acetylcholine receptor-mediated responses in Xenopus oocytes. J Pharmacol Exp Ther 310:1152–1160

    Article  CAS  PubMed  Google Scholar 

  • Oz M, Jackson SN, Woods AS, Morales M, Zhang L (2005) Additive effects of endogenous cannabinoid anandamide and ethanol on α7-nicotinic acetylcholine receptor-mediated responses in Xenopus oocytes. J Pharmacol Exp Ther 313:1272–1280

    Article  CAS  PubMed  Google Scholar 

  • Oz M, Yang K-H, Dinc M, Shippenberg TS (2007) The endogenous cannabinoid anandamide inhibits cromakalim-activated K+ currents in follicle-enclosed Xenopus oocytes. J Pharmacol Exp Ther 323:547–554

    Article  CAS  PubMed  Google Scholar 

  • Oz M, Al Kury L, Keun-Hang SY, Mahgoub M, Galadari S (2014) Cellular approaches to the interaction between cannabinoid receptor ligands and nicotinic acetylcholine receptors. Eur J Pharmacol 731:100–105

    Article  CAS  PubMed  Google Scholar 

  • Pamplona FA, Ferreira J, de Lima OM, Duarte FS, Bento AF, Forner S, Villarinho JG, Bellocchio L, Wotjak CT, Lerner R, Monory K, Lutz B, Canetti C, Matias I, Calixto JB, Marsicano G, Guimarães MZP, Takahashi RN (2012) Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor. Proc Natl Acad Sci U S A 109:21134–21139

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Paugh SW, Cassidy MP, He H, Milstien S, Sim-Selley LJ, Spiegel S, Selley DE (2006) Sphingosine and its analog, the immunosuppressant 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol, interact with the CB1 cannabinoid receptor. Mol Pharmacol 70:41–50

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Pertwee RG (2014) Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications. Proc Nutr Soc 73:96–105

    Article  CAS  PubMed  Google Scholar 

  • Pertwee RG, Howlett AC, Abood ME, Alexander SPH, 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 Central  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Petrucci V, Chicca A, Viveros-Paredes JM, Gertsch J (2014) Peptide endocannabinoids (Pepcans) are PAMs of CB2 receptors and involved in the innate immune response. In: 24th annual symposium on the cannabinoids, International Cannabinoid Research Society, Research Triangle Park, NC, USA, p 62

    Google Scholar 

  • Pinto JC, Potié F, Rice KC, Boring D, Johnson MR, Evans DM, Wilken GH, Cantrell CH, Howlett AC (1994) Cannabinoid receptor binding and agonist activity of amides and esters of arachidonic acid. Mol Pharmacol 46:516–522

    CAS  PubMed  Google Scholar 

  • Poling JS, Rogawski MA, Salem N, Vicini S (1996) Anandamide, an endogenous cannabinoid, inhibits Shaker-related voltage-gated K+ channels. Neuropharmacology 35:983–991

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Price MR, Baillie GL, Thomas A, Stevenson LA, Easson M, Goodwin R, McLean A, McIntosh L, Goodwin G, Walker G, Westwood P, Marrs J, Thomson F, Cowley P, Christopoulos A, Pertwee RG, Ross RA (2005a) Allosteric modulation of the cannabinoid CB1 receptor. Mol Pharmacol 68:1484–1495

    Article  CAS  PubMed  Google Scholar 

  • Price TJ, Patwardhan AM, Flores CM, Hargreaves KM (2005b) A role for the anandamide membrane transporter in TRPV1-mediated neurosecretion from trigeminal sensory neurons. Neuropharmacology 49:25–39

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Qin N, Neeper MP, Liu Y, Hutchinson TL, Lubin ML, Flores CM (2008) TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. J Neurosci 28:6231–6238

    Article  CAS  PubMed  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

    CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Roberts LA, Christie MJ, Connor M (2002) Anandamide is a partial agonist at native vanilloid receptors in acutely isolated mouse trigeminal sensory neurons. Br J Pharmacol 137:421–428

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rockwell CE, Snider NT, Thompson JT, Heuvel JPV, Kaminski NE (2006) Interleukin-2 suppression by 2-arachidonyl glycerol is mediated through peroxisome proliferator-activated receptor γ independently of cannabinoid receptors 1 and 2. Mol Pharmacol 70:101–111

    CAS  PubMed  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 Central  CAS  PubMed  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 156:740–750

    Article  PubMed Central  CAS  PubMed  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 Central  CAS  PubMed  Google Scholar 

  • Sade H, Muraki K, Ohya S, Hatano N, Imaizumi Y (2006) Activation of large-conductance, Ca2+-activated K+ channels by cannabinoids. Am J Physiol Cell Physiol 290:C77–C86

    Article  CAS  PubMed  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 Central  CAS  PubMed  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 Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Sheskin T, Hanuš 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  CAS  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

    CAS  PubMed  Google Scholar 

  • Sigel E, Baur R, Rácz I, Marazzi J, Smart TG, Zimmer A, Gertsch J (2011) The major central endocannabinoid directly acts at GABAA receptors. Proc Natl Acad Sci U S A 108:18150–18155

    Article  PubMed Central  CAS  PubMed  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 U S A 92:7242–7246

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Smart D, Gunthorpe MJ, Jerman JC, Nasir S, Gray J, Muir AI, Chambers JK, Randall AD, Davis JB (2000) The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br J Pharmacol 129:227–230

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Smith PB, Compton DR, Welch SP, Razdan RK, Mechoulam R, Martin BR (1994) The pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice. J Pharmacol Exp Ther 270:219–227

    PubMed  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

    CAS  PubMed  Google Scholar 

  • Spivak CE, Lupica CR, Oz M (2007) The endocannabinoid anandamide inhibits the function of α4β2 nicotinic acetylcholine receptors. Mol Pharmacol 72:1024–1032

    Article  CAS  PubMed  Google Scholar 

  • Spivak CE, Kim W, Liu Q-R, Lupica CR, Doyle ME (2012) Blockade of β-cell KATP channels by the endocannabinoid, 2-arachidonoylglycerol. Biochem Biophys Res Commun 423:13–18

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Starowicz K, Nigam S, Di Marzo V (2007) Biochemistry and pharmacology of endovanilloids. Pharmacol Ther 114:13–33

    Article  CAS  PubMed  Google Scholar 

  • Steffens M, Zentner J, Honegger J, Feuerstein TJ (2005) Binding affinity and agonist activity of putative endogenous cannabinoids at the human neocortical CB1 receptor. Biochem Pharmacol 69:169–178

    Article  CAS  PubMed  Google Scholar 

  • Stella N, Schweitzer P, Piomelli D (1997) A second endogenous cannabinoid that modulates long-term potentiation. Nature 388:773–778

    Article  CAS  PubMed  Google Scholar 

  • Sugiura T, Kondo S, Kodaka T, Tonegawa T, Nakane S, Yamashita A, Ishima Y, Waku K (1996) Enzymatic synthesis of oleamide (cis-9,10-octadenoamide), an endogenous sleep-inducing lipid, by rat brain microsomes. Biochem Mol Biol Int 40:931–938

    CAS  PubMed  Google Scholar 

  • Sun Y, Alexander SPH, Garle MJ, Gibson CL, Hewitt K, Murphy SP, Kendall DA, Bennett AJ (2007) Cannabinoid activation of PPARα; a novel neuroprotective mechanism. Br J Pharmacol 152:734–743

    Article  PubMed Central  CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Tóth BI, Dobrosi N, Dajnoki A, Czifra G, Oláh A, Szöllosi AG, Juhász I, Sugawara K, Paus R, Bíro T (2011) Endocannabinoids modulate human epidermal keratinocyte proliferation and survival via the sequential engagement of cannabinoid receptor-1 and transient receptor potential vanilloid-1. J Invest Dermatol 131:1095–1104

    Article  PubMed  CAS  Google Scholar 

  • Vallée M, Vitiello S, Bellocchio L, Hébert-Chatelain E, Monlezun S, Martin-Garcia E, Kasanetz F, Baillie GL, Panin F, Cathala A, Roullot-Lacarrière V, Fabre S, Hurst DP, Lynch DL, Shore DM, Deroche-Gamonet V, Spampinato U, Revest JM, Maldonado R, Reggio PH, Ross RA, Marsicano G, Piazza PV (2014) Pregnenolone can protect the brain from cannabis intoxication. Science 343:94–98

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Van den Bossche I, Vanheel B (2000) Influence of cannabinoids on the delayed rectifier in freshly dissociated smooth muscle cells of the rat aorta. Br J Pharmacol 131:85–93

    Article  PubMed Central  PubMed  Google Scholar 

  • Vignali M, Benfenati V, Caprini M, Anderova M, Nobile M, Ferroni S (2009) The endocannabinoid anandamide inhibits potassium conductance in rat cortical astrocytes. Glia 57:791–806

    Article  CAS  PubMed  Google Scholar 

  • Vogel Z, Barg J, Levy R, Saya D, Heldman E, Mechoulam R (1993) Anandamide, a brain endogenous compound, interacts specifically with cannabinoid receptors and inhibits adenylate cyclase. J Neurochem 61:352–355

    Article  CAS  PubMed  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 Central  CAS  PubMed  Google Scholar 

  • Wang W, Zhang K, Yan S, Li A, Hu X, Zhang L, Liu C (2011) Enhancement of apamin-sensitive medium afterhyperpolarization current by anandamide and its role in excitability control in cultured hippocampal neurons. Neuropharmacology 60:901–909

    Article  CAS  PubMed  Google Scholar 

  • Xiong W, Hosoi M, Koo B-N, Zhang L (2008) Anandamide inhibition of 5-HT3A receptors varies with receptor density and desensitization. Mol Pharmacol 73:314–322

    Article  CAS  PubMed  Google Scholar 

  • Xiong W, Wu X, Li F, Cheng K, Rice KC, Lovinger DM, Zhang L (2012) A common molecular basis for exogenous and endogenous cannabinoid potentiation of glycine receptors. J Neurosci 32:5200–5208

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yang Z, Aubrey KR, Alroy I, Harvey RJ, Vandenberg RJ, Lynch JW (2008) Subunit-specific modulation of glycine receptors by cannabinoids and N-arachidonyl-glycine. Biochem Pharmacol 76:1014–1023

    Article  CAS  PubMed  Google Scholar 

  • Ye RD, Boulay F, Wang JM, Dahlgren C, Gerard C, Parmentier M, Serhan CN, Murphy PM (2009) International union of basic and clinical pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family. Pharmacol Rev 61:119–161

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  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 Central  CAS  PubMed  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

    Article  CAS  PubMed  Google Scholar 

  • Zygmunt PM, Ermund A, Movahed P, Andersson DA, Simonsen C, Jönsson BAG, Blomgren A, Birnir B, Bevan S, Eschalier A, Mallet C, Gomis A, Högestätt ED (2013) Monoacylglycerols activate TRPV1—a link between phospholipase C and TRPV1. PLoS One 8:e81618

    Article  PubMed Central  PubMed  CAS  Google Scholar 

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    Roger G. Pertwee

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Pertwee, R.G. (2015). Endocannabinoids and Their Pharmacological Actions. In: Pertwee, R. (eds) Endocannabinoids. Handbook of Experimental Pharmacology, vol 231. Springer, Cham. https://doi.org/10.1007/978-3-319-20825-1_1

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