Molecular Targets of the Phytocannabinoids: A Complex Picture

  • Paula Morales
  • Dow P. Hurst
  • Patricia H. ReggioEmail author
Part of the Progress in the Chemistry of Organic Natural Products book series (POGRCHEM, volume 103)


For centuries, hashish and marihuana, both derived from the Indian hemp Cannabis sativa L., have been used for their medicinal, as well as, their psychotropic effects. These effects are associated with the phytocannabinoids which are oxygen containing C21 aromatic hydrocarbons found in Cannabis sativa L. To date, over 120 phytocannabinoids have been isolated from Cannabis. For many years, it was assumed that the beneficial effects of the phytocannabinoids were mediated by the cannabinoid receptors, CB1 and CB2. However, today we know that the picture is much more complex, with the same phytocannabinoid acting at multiple targets. This contribution focuses on the molecular pharmacology of the phytocannabinoids, including Δ9-THC and CBD, from the prospective of the targets at which these important compounds act.


Phytocannabinoid Δ9-THC Δ8-THC CBN CBD CBG CBC THCV CBV CBDV CBND CBE CBL CBT GPCR CB1 receptor CB2 receptor PPARγ Glycine receptor TRPV1 channel TRPA1 channel TRPM8 channel 



The authors acknowledge research support from NIH/NIDA grants R01 DA003934 and K05 DA021358 (P.H.R.).


  1. 1.
    Mechoulam R, Gaoni Y (1967) The absolute configuration of Δ1-tetrahydrocannabinol, the major active constituent of hashish. Tetrahedron Lett 8:1109CrossRefGoogle Scholar
  2. 2.
    Pomorska DK, do-Rego J-C, do-Rego J-L, Zubrzycka M, Janecka A (2016) Opioid and cannabinoid system in food intake. Curr Pharm Des 22:1361CrossRefGoogle Scholar
  3. 3.
    Boychuk DG, Goddard G, Mauro G, Orellana MF (2015) The effectiveness of cannabinoids in the management of chronic nonmalignant neuropathic pain: a systematic review. J Oral Facial Pain Headache 29:7CrossRefGoogle Scholar
  4. 4.
    Novack GD (2016) Cannabinoids for treatment of glaucoma. Curr Opin Ophthalmol 27:146CrossRefGoogle Scholar
  5. 5.
    Phillips RS, Friend AJ, Gibson F, Houghton E, Gopaul S, Craig JV, Pizer B (2016) Antiemetic medication for prevention and treatment of chemotherapy-induced nausea and vomiting in childhood. Cochrane Database Syst Rev 2:CD007786Google Scholar
  6. 6.
    Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO (2007) Cannabidiol—recent advances. Chem Biodivers 4:1678CrossRefGoogle Scholar
  7. 7.
    ElSohly MA, Gul W (2014) Constituents of Cannabis sativa. In: Pertwee RG (ed) Handbook of Cannabis. Oxford University Press, Oxford, p 3CrossRefGoogle Scholar
  8. 8.
    Howlett A, Barth F, Bonner T, Cabral G, Casellas P, Devane W, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54:161CrossRefGoogle Scholar
  9. 9.
    Bolognini D, Cascio MG, Parolaro D, Pertwee RG (2012) AM630 behaves as a protean ligand at the human cannabinoid CB2 receptor. Br J Pharmacol 165:2561CrossRefGoogle Scholar
  10. 10.
    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 105:269CrossRefGoogle Scholar
  11. 11.
    Drmota P, Greasley P, Groblewski T (2004) Screening assays for cannabinoid-ligand type modulators. AstraZeneca Patent WO2004074844Google Scholar
  12. 12.
    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 152:1092CrossRefGoogle Scholar
  13. 13.
    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 beta-arrestin PathHunter assay. J Biol Chem 284:12328CrossRefGoogle Scholar
  14. 14.
    Oka S, Nakajima K, Yamashita A, Kishimoto S, Sugiura T (2007) Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem Biophys Res Commun 362:928CrossRefGoogle Scholar
  15. 15.
    Crombie L, Ponsford R, Shani A, Yagnitinsky B, Mechoulam R (1968) Hashish components. Photochemical production of cannabicyclol from cannabichromene. Tetrahedron Lett 9:5771CrossRefGoogle Scholar
  16. 16.
    Kapur A, Zhao P, Sharir H, Bai Y, Caron MG, Barak LS, Abood ME (2009) Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands. J Biol Chem 284:29817CrossRefGoogle Scholar
  17. 17.
    Anavi-Goffer S, Baillie G, Irving AJ, Gertsch J, Greig IR, Pertwee RG, Ross RA (2012) Modulation of l-α-lysophosphatidylinositol/GPR55 mitogen-activated protein kinase (MAPK) signaling by cannabinoids. J Biol Chem 287:91CrossRefGoogle Scholar
  18. 18.
    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 137:589CrossRefGoogle Scholar
  19. 19.
    McHugh D, Roskowski D, Xie S, Bradshaw HB (2014) Δ9-THC and N-arachidonoyl glycine regulate BV-2 microglial morphology and cytokine release plasticity: implications for signaling at GPR18. Front Pharmacol 4:1CrossRefGoogle Scholar
  20. 20.
    Shi B, Yang R, Wang X, Liu H, Zou L, Hu X, Wu J, Zou A, Liu L (2012) Inhibition of 5-HT3 receptors-activated currents by cannabinoids in rat trigeminal ganglion neurons. J Huazhong Univ Sci Technolog 32:265CrossRefGoogle Scholar
  21. 21.
    Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E (2006) Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch Pharmacol 372:354CrossRefGoogle Scholar
  22. 22.
    O’Sullivan SEO, Kendall DA, Randall MD (2006) Further characterization of the time-dependent vascular effects of Δ9-tetrahydrocannabinol. J Pharmacol Exp Ther 317:428CrossRefGoogle Scholar
  23. 23.
    Vara D, Morell C, Rodríguez-Henche N, Diaz-Laviada I (2013) Involvement of PPARγ in the antitumoral action of cannabinoids on hepatocellular carcinoma. Cell Death Dis 4, e618CrossRefGoogle Scholar
  24. 24.
    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 28:6231CrossRefGoogle Scholar
  25. 25.
    De Petrocellis L, Ligresti A, Moriello AS, Allar M, Bisogno T, Petrosino S, Stott CG, Di Marzo V (2011) Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol 163:1479CrossRefGoogle Scholar
  26. 26.
    Razdan RK, Dalzell HC, Herlihy P, Howes JF (1976) Hashish. Unsaturated side-chain analogues of Δ8-tetrahydrocannabinol with potent biological activity. J Med Chem 19:1328CrossRefGoogle Scholar
  27. 27.
    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 7:2905CrossRefGoogle Scholar
  28. 28.
    Järbe TU, Henriksson BG (1973) Effects of Δ8-THC, and Δ9-THC on the acquisition of a discriminative positional habit in rats. The transitions between normal and tetrahydrocannabinol-induced states on reversal learning. Psychopharmacologia 31:321CrossRefGoogle Scholar
  29. 29.
    Harvey DJ (1990) Stability of cannabinoids in dried samples of Cannabis dating from around 1896–1905. J Ethnopharmacol 28:117CrossRefGoogle Scholar
  30. 30.
    Pertwee RG, Ross RA, Craib SJ, Thomas A (2002) (−)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens. Eur J Pharmacol 456:99CrossRefGoogle Scholar
  31. 31.
    Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, Breuer A, Mechoulam R (1997) Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase. J Med Chem 40:3228CrossRefGoogle Scholar
  32. 32.
    Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG (2007) Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 150:613CrossRefGoogle Scholar
  33. 33.
    Laprairie RB, Bagher AM, Kelly MEM, Denovan-Wright EM (2015) Cannabidiol is a negative allosteric modulator of the type 1 cannabinoid receptor. Br J Pharmacol 20:4790CrossRefGoogle Scholar
  34. 34.
    Morales P, Goya P, Jagerovic N, Hernandez-Folgado L (2016) Allosteric modulators of the CB1 cannabinoid receptor: a structural update review. Cannabis Cannabinoid Res 1:22CrossRefGoogle Scholar
  35. 35.
    Ford LA, Roelofs AJ, Anavi-Goffer S, Mowat L, Simpson DG, Irving AJ, Rogers MJ, Rajnicek AM, Ross RA (2010) A role for l-alpha-lysophosphatidylinositol and GPR55 in the modulation of migration, orientation and polarization of human breast cancer cells. Br J Pharmacol 160:762CrossRefGoogle Scholar
  36. 36.
    Whyte LS, Ryberg E, Sims NA, Ridge SA, Mackie K, Greasley PJ, Ross RA, Rogers MJ (2009) The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc Natl Acad Sci U S A 106:16511CrossRefGoogle Scholar
  37. 37.
    Russo EB, Burnett A, Hall B, Parker KK (2005) Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 30:1037CrossRefGoogle Scholar
  38. 38.
    Rock EM, Bolognini D, Limebeer CL, Cascio MG, Anavi-Goffer S, Fletcher PJ, Mechoulam R, Pertwee RG, Parker LA (2012) Cannabidiol, a nonpsychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT1A somatodendritic autoreceptors in the dorsal raphe nucleus. Br J Pharmacol 165:2620CrossRefGoogle Scholar
  39. 39.
    Yang K-H, Galadari S, Isaev D, Petroianu G, Shippenberg TS, Oz M (2010) The nonpsychoactive cannabinoid cannabidiol inhibits 5-hydroxytryptamine3A receptor-mediated currents in Xenopus laevis oocytes. J Pharmacol Exp Ther 333:547CrossRefGoogle Scholar
  40. 40.
    Gonca E, Darıcı F (2014) The effect of cannabidiol on ischemia/reperfusion-induced ventricular arrhythmias: the role of adenosine A1 receptors. J Cardiovasc Pharmacol Ther 1:76Google Scholar
  41. 41.
    O’Sullivan SE, Sun Y, Bennett AJ, Randall MD, Kendall DA (2009) Time-dependent vascular actions of cannabidiol in the rat aorta. Eur J Pharmacol 612:61CrossRefGoogle Scholar
  42. 42.
    Esposito G, Scuderi C, Valenza M, Togna GI, Latina V, de Filippis D, Cipriano M, Carratù MR, Iuvone T, Steardo L (2011) Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PLoS One 6:e28668CrossRefGoogle Scholar
  43. 43.
    Scuderi C, Steardo L, Esposito G (2014) Cannabidiol promotes amyloid precursor protein ubiquitination and reduction of beta amyloid expression in SHSY5YAPP+ cells through PPARγ involvement. Phytother Res 28:1007CrossRefGoogle Scholar
  44. 44.
    Ahrens J, Demir R, Leuwer M, De La Roche J, Krampfl K, Foadi N, Karst M, Haeseler G (2009) The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-beta glycine receptor function. Pharmacology 83:217CrossRefGoogle Scholar
  45. 45.
    Xiong W, Cui T, Cheng K, Yang F, Chen SR, Willenbring D, Guan Y, Pan HL, Ren K, Xu Y, Zhang L (2012) Cannabinoids suppress inflammatory and neuropathic pain by targeting alpha3 glycine receptors. J Exp Med 209:1121CrossRefGoogle Scholar
  46. 46.
    Bakas T, Devenish S, Van Nieuwenhuizen P, Arnold J, McGregor I, Collins M (2016) The actions of cannabidiol and 2-arachidonyl glycerol on GABA-A receptors. In: 26th Annual Symposium on the Cannabinoids, International Cannabinoid Research Society, Bukovina, Poland, p 28Google Scholar
  47. 47.
    Rosenthaler S, Pöhn B, Kolmanz C, Nguyen Huu C, Krewenka C, Huber A, Kranner B, Rausch WD, Moldzio R (2014) Differences in receptor binding affinity of several phytocannabinoids do not explain their effects on neural cell cultures. Neurotoxicol Teratol 46:49CrossRefGoogle Scholar
  48. 48.
    Izzo A, Borrelli F, Capasso R, Di Marzo V, Mechoulam R (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 30:515CrossRefGoogle Scholar
  49. 49.
    Thomas A, Stevenson LA, Wease KN, Price MR, Baillie G, Ross RA, Pertwee RG (2005) Evidence that the plant cannabinoid Δ9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist. Br J Pharmacol 146:917CrossRefGoogle Scholar
  50. 50.
    Cascio MG, Gauson LA, Stevenson LA, Ross RA, Pertwee RG (2010) Evidence that the plant cannabinoid cannabigerol is a highly potent α2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. Br J Pharmacol 159:129CrossRefGoogle Scholar
  51. 51.
    Bolognini D, Costa B, Maione S, Comelli F, Marini P, Di Marzo V, Parolaro D, Ross RA, Gauson LA, Cascio MG, Pertwee RG (2010) The plant cannabinoid Δ9-tetrahydrocannabivarin can decrease signs of inflammation and inflammatory pain in mice. Br J Pharmacol 160:677CrossRefGoogle Scholar
  52. 52.
    Pertwee RG (2005) Pharmacological actions of cannabinoids. Handb Exp Pharmacol 168:1CrossRefGoogle Scholar
  53. 53.
    Pertwee RG (1999) Pharmacology of cannabinoid receptor ligands. Curr Med Chem 6:635Google Scholar
  54. 54.
    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 165:2414CrossRefGoogle Scholar
  55. 55.
    Xiong W, Cheng K, Cui T, Godlewski G, Rice KC, Xu Y, Zhang L (2011) Cannabinoid potentiation of glycine receptors contributes to Cannabis-induced analgesia. Nat Chem Biol 7:296CrossRefGoogle Scholar
  56. 56.
    Hejazi N, Zhou C, Oz M, Sun H, Ye JH, Zhang L (2006) Delta9-tetrahydrocannabinol and endogenous cannabinoid anandamide directly potentiate the function of glycine receptors. Mol Pharmacol 69:991Google Scholar
  57. 57.
    De Petrocellis L, Orlando P, Moriello AS, Aviello G, Stott C, Izzo AA, di Marzo V (2012) Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol 204:255CrossRefGoogle Scholar
  58. 58.
    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 325:1007CrossRefGoogle Scholar
  59. 59.
    Leighty EG, Fentiman AF, Foltz RL (1976) Long-retained metabolites of Δ9- and Δ8-tetrahydrocannabinols identified as novel fatty acid conjugates. Res Commun Chem Pathol Pharmacol 14:13Google Scholar
  60. 60.
    Razdan RK (1986) Structure-activity relationships in cannabinoids. Pharmacol Rev 38:75Google Scholar
  61. 61.
    Järbe TU, Henriksson BG (1973) Acute effects of two tetrahydrocannabinols (Δ9-THC and Δ8-THC) on water intake in water deprived rats: implications for behavioral studies on marijuana compounds. Psychopharmacologia 30:315–22Google Scholar
  62. 62.
    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 124:619CrossRefGoogle Scholar
  63. 63.
    McPartland JM, Glass M, Pertwee RG (2007) Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences. Br J Pharmacol 152:583CrossRefGoogle Scholar
  64. 64.
    Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol 153:199CrossRefGoogle Scholar
  65. 65.
    Pertwee RG, Thomas A, Stevenson LA, Ross RA, Varvel SA, Lichtman AH, Martin BR, Razdan RK (2007) The psychoactive plant cannabinoid, Δ9-tetrahydrocannabinol, is antagonized by Δ8- and Δ9-tetrahydrocannabivarin in mice in vivo. Br J Pharmacol 150:586CrossRefGoogle Scholar
  66. 66.
    McPartland JM, Duncan M, Di Marzo V, Pertwee RG (2015) Are cannabidiol and Δ9-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol 172:737CrossRefGoogle Scholar
  67. 67.
    Pertwee RG (1972) The ring test: a quantitative method for assessing the “cataleptic” effect of cannabis in mice. Br J Pharmacol 46:753CrossRefGoogle Scholar
  68. 68.
    Cascio MG, Zamberletti E, Marini P, Parolaro D, Pertwee RG (2015) The phytocannabinoid, Δ9-tetrahydrocannabivarin, can act through 5-HT1A receptors to produce antipsychotic effects. Br J Pharmacol 172:1305CrossRefGoogle Scholar
  69. 69.
    Merkus FW (1971) Cannabivarin, a new constituent of hashish. Pharm Weekbl 106:69Google Scholar
  70. 70.
    Merkus FW (1971) Cannabivarin and tetrahydrocannabivarin, two new constituents of hashish. Nature 232:579CrossRefGoogle Scholar
  71. 71.
    Bailey K, Gagné D (1975) Distinction of synthetic cannabidiol, cannabichromene, and cannabivarin by GLC using on-column methylation. J Pharm Sci 64:1719CrossRefGoogle Scholar
  72. 72.
    Hill TDM, Cascio MG, Romano B, Duncan M, Pertwee RG, Williams CM, Whalley BJ, Hill AJ (2013) Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. Br J Pharmacol 170:679CrossRefGoogle Scholar
  73. 73.
    Lousberg RJJC, Bercht CAL, van Ooyen R, Spronck HJW (1977) Cannabinodiol: conclusive identification and synthesis of a new cannabinoid from Cannabis sativa. Phytochemistry 16:595CrossRefGoogle Scholar
  74. 74.
    ElSohly MA, Slade D (2005) Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 78:539CrossRefGoogle Scholar
  75. 75.
    Shani A, Mechoulam R (1974) Cannabielsoic acids: isolation and synthesis by a novel oxidative cyclization. Tetrahedron 30:2437CrossRefGoogle Scholar
  76. 76.
    Ujváry I, Hanuš L (2016) Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy. Cannabis Cannabinoid Res 1:90CrossRefGoogle Scholar
  77. 77.
    Hartsel SC, Loh WH, Robertson LW (1983) Biotransformation of cannabidiol to cannabielsoin by suspension cultures of Cannabis sativa and Saccharum officinarum. Planta Med 48:17CrossRefGoogle Scholar
  78. 78.
    Yamamoto I, Gohda H, Narimatsu S, Watanabe K, Yoshimura H (1991) Cannabielsoin as a new metabolite of cannabidiol in mammals. Pharmacol Biochem Behav 40:541CrossRefGoogle Scholar
  79. 79.
    Vree TB, Breimer DD, van Ginneken CAM, van Rossum JM (1972) Identification of cannabicyclol with a pentyl or propyl side-chain by means of combined gas chromatography—mass spectrometry. J Chromatogr A 74:124CrossRefGoogle Scholar
  80. 80.
    Obata Y, Ishikawa Y (1966) Studies on the constituents of hemp plant (Cannabis sativa L.). Agric Biol Chem 30:619Google Scholar
  81. 81.
    Elsohly MA, El-Feraly FS, Turner CE (1977) Isolation and characterization of (+)-cannabitriol and (−)-10-ethoxy-9-hydroxy-Δ6a[10a]-tetrahydrocannabinol: two new cannabinoids from Cannabis sativa L. extract. Lloydia 40:275Google Scholar
  82. 82.
    Brogan AP, Eubanks LM, Koob GF, Dickerson TJ, Janda KD (2007) Antibody-catalyzed oxidation of Δ9-tetrahydrocannabinol. J Am Chem Soc 129:3698CrossRefGoogle Scholar
  83. 83.
    Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561CrossRefGoogle Scholar
  84. 84.
    Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61CrossRefGoogle Scholar
  85. 85.
    Hurst DP, Schmeisser M, Reggio PH (2013) Endogenous lipid activated G protein-coupled receptors: emerging structural features from crystallography and molecular dynamics simulations. Chem Phys Lipids 169:46CrossRefGoogle Scholar
  86. 86.
    Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83CrossRefGoogle Scholar
  87. 87.
    Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K (1995) 2-Arachidonoylgylcerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89CrossRefGoogle Scholar
  88. 88.
    Devane W, Hanus L, Breuer A, Pertwee R, Stevenson L, 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 258:1946CrossRefGoogle Scholar
  89. 89.
    Di Marzo V (2008) Endocannabinoids: synthesis and degradation. Rev Physiol Biochem Pharmacol 160:1Google Scholar
  90. 90.
    Dinh TP, Freund TF, Piomelli D (2002) A role for monoglyceride lipase in 2-arachidonoylglycerol inactivation. Chem Phys Lipids 121:149CrossRefGoogle Scholar
  91. 91.
    Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF (2002) Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science 298:1793CrossRefGoogle Scholar
  92. 92.
    Diana MA, Marty A (2004) Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol 142:9CrossRefGoogle Scholar
  93. 93.
    Hanson MA, Roth CB, Jo E, Griffith MT, Scott FL, Reinhart G, Desale H, Clemons B, Cahalan SM, Schuerer SC, Sanna MG, Han GW, Kuhn P, Rosen H, Stevens RC (2012) Crystal structure of a lipid G protein-coupled receptor. Science 335:851CrossRefGoogle Scholar
  94. 94.
    Srivastava A, Yano J, Hirozane Y, Kefala G, Gruswitz F, Snell G, Lane W, Ivetac A, Aertgeerts K, Nguyen J, Jennings A, Okada K (2014) High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature 513:124CrossRefGoogle Scholar
  95. 95.
    Hurst DP, Grossfield A, Lynch DL, Feller S, Romo TD, Gawrisch K, Pitman MC, Reggio PH (2010) A lipid pathway for ligand binding is necessary for a cannabinoid G protein-coupled receptor. J Biol Chem 285:17954CrossRefGoogle Scholar
  96. 96.
    Picone RP, Khanolkar AD, Xu W, Ayotte LA, Thakur GA, Hurst DP, Abood ME, Reggio PH, Fournier DJ, Makriyannis A (2005) (−)-7′-Isothiocyanato-11-hydroxy-1′, 1′-dimethylheptylhexahydrocannabinol (AM841), a high-affinity electrophilic ligand, interacts covalently with a cysteine in helix six and activates the CB1 cannabinoid receptor. Mol Pharmacol 68:1623Google Scholar
  97. 97.
    Pei Y, Mercier RW, Anday JK, Thakur G, Zvonok AM, Hurst D, Reggio PH, Janero DR, Makriyannis A (2008) Ligand-binding architecture of human CB2 cannabinoid receptor: evidence for receptor subtype-specific binding motif and modeling GPCR activation. Chem Biol 15:1207CrossRefGoogle Scholar
  98. 98.
    O’Sullivan SE (2016) An update on peroxisome proliferator-activated receptor (PPAR) activation by cannabinoids. Br J Pharmacol 173:1899CrossRefGoogle Scholar
  99. 99.
    O’Sullivan SE (2013) Cannabinoid activation of peroxisome proliferator-activated receptors: an update and review of the physiological relevance. Wiley Interdiscip Rev Membr Transp Signal 2:17CrossRefGoogle Scholar
  100. 100.
    O’Sullivan SE (2007) Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol 152:576CrossRefGoogle Scholar
  101. 101.
    Burstein S (2005) PPAR-gamma: a nuclear receptor with affinity for cannabinoids. Life Sci 77:1674CrossRefGoogle Scholar
  102. 102.
    Sun Y, Alexander SPH, Kendall DA, Bennett AJ (2006) Cannabinoids and PPARalpha signalling. Biochem Soc Trans 34:1095CrossRefGoogle Scholar
  103. 103.
    Ambrosio ALB, Dias SMG, Polikarpov I, Zurier RB, Burstein SH, Garratt RC (2007) Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor. J Biol Chem 282:18625CrossRefGoogle Scholar
  104. 104.
    Kozak KR, Gupta RA, Moody JS, Ji C, Boeglin WE, DuBois RN, Brash AR, Marnett LJ (2002) 15-Lipoxygenase metabolism of 2-arachidonylglycerol. Generation of a peroxisome proliferator-activated receptor alpha agonist. J Biol Chem 277:23278CrossRefGoogle Scholar
  105. 105.
    Hughes MLR, Liu B, Halls ML, Wagstaff KM, Patil R, Velkov T, Jans DA, Bunnett NW, Scanlon MJ, Porter CJH (2015) Fatty acid-binding proteins 1 and 2 differentially modulate the activation of peroxisome proliferator-activated receptor in a ligand-selective manner. J Biol Chem 290:13895CrossRefGoogle Scholar
  106. 106.
    Yano M, Matsumura T, Senokuchi T, Ishii N, Murata Y, Taketa K, Motoshima H, Taguchi T, Sonoda K, Kukidome D, Takuwa Y, Kawada T, Brownlee M, Nishikawa T, Araki E (2007) Statins activate peroxisome proliferator-activated receptor gamma through extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2 expression in macrophages. Circ Res 100:1442CrossRefGoogle Scholar
  107. 107.
    Sun Y, Alexander SP, Garle MJ, Gibson CL, Hewitt K, Murphy SP, Kendall DA, Bennett AJ (2007) Cannabinoid activation of PPAR alpha: a novel neuroprotective mechanism. Br J Pharmacol 152:734CrossRefGoogle Scholar
  108. 108.
    Takeda S, Ikeda E, Su S, Harada M, Okazaki H, Yoshioka Y, Nishimura H, Ishii H, Kakizoe K, Taniguchi A, Tokuyasu M, Himeno T, Watanabe K, Omiecinski CJ, Aramaki H (2014) Δ9-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: possible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells. Toxicology 326:18CrossRefGoogle Scholar
  109. 109.
    O’Sullivan SE, Tarling EJ, Bennett AJ, Kendall DA, Randall MD (2005) Novel time-dependent vascular actions of Δ9-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma. Biochem Biophys Res Commun 337:824CrossRefGoogle Scholar
  110. 110.
    Granja AG, Carrillo-Salinas F, Pagani A, Gomez-Canas M, Negri R, Navarrete C, Mecha M, Mestre L, Fiebich BL, Cantarero I, Calzado MA, Bellido ML, Fernandez-Ruiz J, Appendino G, Guaza C, Munoz E (2012) A cannabigerol quinone alleviates neuroinflammation in a chronic model of multiple sclerosis. J Neuroimmune Pharmacol 7:1002CrossRefGoogle Scholar
  111. 111.
    Hind WH, England TJ, O’Sullivan SE (2016) Cannabidiol protects an in vitro model of the blood–brain barrier from oxygen-glucose deprivation via PPARγ and 5-HT1A receptors. Br J Pharmacol 173:815CrossRefGoogle Scholar
  112. 112.
    Alhamoruni A, Wright KL, Larvin M, O’Sullivan SE (2012) Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability. Br J Pharmacol 165:2598CrossRefGoogle Scholar
  113. 113.
    Alhamoruni A, Lee AC, Wright KL, Larvin M, Sullivan SEO (2010) Pharmacological effects of cannabinoids on the Caco-2 cell culture model of intestinal permeability. Pharmacology 335:92Google Scholar
  114. 114.
    Ahrens J, Leuwer M, Demir R, Krampfl K, De La Roche J, Foadi N, Karst M, Haeseler G (2009) Positive allosteric modulatory effects of ajulemic acid at strychnine-sensitive glycine α1- and α1β- receptors. Naunyn Schmiedebergs Arch Pharmacol 379:371CrossRefGoogle Scholar
  115. 115.
    Demir R, Leuwer M, De La Roche J, Krampfl K, Foadi N, Karst M, Dengler R, Haeseler G, Ahrens J (2009) Modulation of glycine receptor function by the synthetic cannabinoid HU210. Pharmacology 83:270CrossRefGoogle Scholar
  116. 116.
    Dutertre S, Becker CM, Betz H (2012) Inhibitory glycine receptors: an update. J Biol Chem 287:40216CrossRefGoogle Scholar
  117. 117.
    Betz H, Laube B (2006) Glycine receptors: recent insights into their structural organization and functional diversity. J Neurochem 97:1600CrossRefGoogle Scholar
  118. 118.
    Foadi N, Leuwer M, Demir R, Dengler R, Buchholz V, De La Roche J, Karst M, Haeseler G, Ahrens J (2010) Lack of positive allosteric modulation of mutated α1S267I glycine receptors by cannabinoids. Naunyn Schmiedebergs Arch Pharmacol 381:477CrossRefGoogle Scholar
  119. 119.
    Christie MJ, Vaughan CW (2011) Receptors: cannabis medicine without a high. Nat Chem Biol 7:249CrossRefGoogle Scholar
  120. 120.
    Wu L, Sweet T, Clapham DE (2010) International union of basic and clinical pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family. Pharmacol Rev 62:381CrossRefGoogle Scholar
  121. 121.
    Moran MM, McAlexander MA, Bíró T, Szallasi A (2011) Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov 10:601CrossRefGoogle Scholar
  122. 122.
    Di Marzo V, De Petrocellis L (2010) Endocannabinoids as regulators of transient receptor potential (TRP) channels: a further opportunity to develop new endocannabinoid-based therapeutic drugs. Curr Med Chem 17:1430CrossRefGoogle Scholar
  123. 123.
    Akopian AN, Ruparel NB, Jeske NA, Patwardhan A, Hargreaves M (2009) Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia. Trends Pharmacol Sci 30:79CrossRefGoogle Scholar
  124. 124.
    Pertwee RG, Howlett AC, Abood ME, Alexander SPH, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev 62:588CrossRefGoogle Scholar
  125. 125.
    Caterina MJ (2014) TRP channel cannabinoid receptors in skin sensation, homeostasis, and inflammation. ACS Chem Neurosci 5:1107CrossRefGoogle Scholar
  126. 126.
    Gao Y, Cao E, Julius D, Cheng Y (2016) TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action. Nature 534:347CrossRefGoogle Scholar
  127. 127.
    Venkatachalam K, Montell C (2007) TRP channels. Annu Rev Biochem 76:387CrossRefGoogle Scholar
  128. 128.
    Anand U, Otto WR, Sanchez-Herrera D, Facer P, Yiangou Y, Korchev Y, Birch R, Benham C, Bountra C, Chessell IP, Anand P (2008) Cannabinoid receptor CB2 localisation and agonist-mediated inhibition of capsaicin responses in human sensory neurons. Pain 138:667CrossRefGoogle Scholar
  129. 129.
    Price TJ, Patwardhan A, Akopian AN, Hargreaves KM, Flores CM (2004) Modulation of trigeminal sensory neuron activity by the dual cannabinoid-vanilloid agonists anandamide, N-arachidonoyl-dopamine and arachidonyl-2-chloroethylamide. Br J Pharmacol 141:1118CrossRefGoogle Scholar
  130. 130.
    Jordt SE, Julius D (2002) Molecular basis for species-specific sensitivity to “hot” chili peppers. Cell 108:421CrossRefGoogle Scholar
  131. 131.
    Iannotti FA, Hill CL, Leo A, Alhusaini A, Soubrane C, Mazzarella E, Russo E, Whalley BJ, Di Marzo V, Stephens GJ (2014) Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci 5:1131CrossRefGoogle Scholar
  132. 132.
    Nabissi M, Morelli MB, Santoni M, Santoni G (2013) Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis 34:48CrossRefGoogle Scholar
  133. 133.
    McKemy DD (2005) How cold is it? TRPM8 and TRPA1 in the molecular logic of cold sensation. Mol Pain 1:16Google Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Paula Morales
    • 1
  • Dow P. Hurst
    • 1
  • Patricia H. Reggio
    • 1
    Email author
  1. 1.Chemistry and Biochemistry DepartmentUNC GreensboroGreensboroUSA

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