Cannabinoids as Modulators of Cell Death: Clinical Applications and Future Directions

  • B. M. Fonseca
  • N. A. Teixeira
  • G. Correia-da-Silva
Part of the Reviews of Physiology, Biochemistry and Pharmacology book series (REVIEWS, volume 173)


Endocannabinoids are bioactive lipids that modulate various physiological processes through G-protein-coupled receptors (CB1 and CB2) and other putative targets. By sharing the activation of the same receptors, some phytocannabinoids and a multitude of synthetic cannabinoids mimic the effects of endocannabinoids. In recent years, a growing interest has been dedicated to the study of cannabinoids properties for their analgesic, antioxidant, anti-inflammatory and neuroprotective effects. In addition to these well-recognized effects, various studies suggest that cannabinoids may affect cell survival, cell proliferation or cell death. These observations indicate that cannabinoids may play an important role in the regulation of cellular homeostasis and, thus, may contribute to tissue remodelling and cancer treatment. For a long time, the study of cannabinoid receptor signalling has been focused on the classical adenylyl cyclase/cyclic AMP/protein kinase A (PKA) pathway. However, this pathway does not totally explain the wide array of biological responses to cannabinoids. In addition, the diversity of receptors and signalling pathways that endocannabinoids modulate offers an interesting opportunity for the development of specific molecules to disturb selectively the endogenous system. Moreover, emerging evidences suggest that cannabinoids ability to limit cell proliferation and to induce tumour-selective cell death may offer a novel strategy in cancer treatment. This review describes the main properties of cannabinoids in cell death and attempts to clarify the different pathways triggered by these compounds that may help to understand the complexity of respective molecular mechanisms and explore the potential clinical benefit of cannabinoids use in cancer therapies.


Apoptosis Autophagy Cancer Cannabinoids 


  1. Almada M, Piscitelli F, Fonseca BM, Di Marzo V, Correia-da-Silva G, Teixeira N (2015) Anandamide and decidual remodelling: COX-2 oxidative metabolism as a key regulator. Biochim Biophys Acta 1851(11):1473–1481. doi: 10.1016/j.bbalip.2015.08.011 PubMedCrossRefGoogle Scholar
  2. Bifulco M, Laezza C, Valenti M, Ligresti A, Portella G, Dim V (2004) A new strategy to block tumor growth by inhibiting endocannabinoid inactivation. FASEB J 18(13):1606–1608. doi: 10.1096/fj.04-1754fje PubMedGoogle Scholar
  3. Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, Matias I, Schiano-Moriello A, Paul P, Williams EJ, Gangadharan U, Hobbs C, Di Marzo V, Doherty P (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol 163(3):463–468. doi: 10.1083/jcb.200305129 PubMedPubMedCentralCrossRefGoogle Scholar
  4. Blazquez C, Galve-Roperh I, Guzman M (2000) De novo-synthesized ceramide signals apoptosis in astrocytes via extracellular signal-regulated kinase. FASEB J 14(14):2315–2322. doi: 10.1096/fj.00-0122com PubMedCrossRefGoogle Scholar
  5. Blazquez C, Salazar M, Carracedo A, Lorente M, Egia A, Gonzalez-Feria L, Haro A, Velasco G, Guzman M (2008) Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. Cancer Res 68(6):1945–1952. doi: 10.1158/0008-5472.CAN-07-5176 PubMedCrossRefGoogle Scholar
  6. Bouaboula M, Poinot-Chazel C, Bourrie B, Canat X, Calandra B, Rinaldi-Carmona M, Le Fur G, Casellas P (1995) Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. Biochem J 312(Pt 2):637–641PubMedPubMedCentralCrossRefGoogle Scholar
  7. Caffarel MM, Sarrio D, Palacios J, Guzman M, Sanchez C (2006) Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation. Cancer Res 66(13):6615–6621. doi: 10.1158/0008-5472.CAN-05-4566 PubMedCrossRefGoogle Scholar
  8. Caffarel MM, Moreno-Bueno G, Cerutti C, Palacios J, Guzman M, Mechta-Grigoriou F, Sanchez C (2008) JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene 27(37):5033–5044. doi: 10.1038/onc.2008.145 PubMedCrossRefGoogle Scholar
  9. Carracedo A, Gironella M, Lorente M, Garcia S, Guzman M, Velasco G, Iovanna JL (2006) Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res 66(13):6748–6755. doi: 10.1158/0008-5472.CAN-06-0169 PubMedCrossRefGoogle Scholar
  10. Casanova ML, Blazquez C, Martinez-Palacio J, Villanueva C, Fernandez-Acenero MJ, Huffman JW, Jorcano JL, Guzman M (2003) Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 111(1):43–50. doi: 10.1172/JCI16116 PubMedPubMedCentralCrossRefGoogle Scholar
  11. 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(24):7033–7040. doi: 10.1093/emboj/20.24.7033 PubMedPubMedCentralCrossRefGoogle Scholar
  12. Cianchi F, Papucci L, Schiavone N, Lulli M, Magnelli L, Vinci MC, Messerini L, Manera C, Ronconi E, Romagnani P, Donnini M, Perigli G, Trallori G, Tanganelli E, Capaccioli S, Masini E (2008) Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha – mediated ceramide De novo synthesis in colon cancer cells. Clin Cancer Res 14(23):7691–7700. doi: 10.1158/1078-0432.CCR-08-0799 PubMedCrossRefGoogle Scholar
  13. Contassot E, Tenan M, Schnuriger V, Pelte MF, Dietrich PY (2004) Arachidonyl ethanolamide induces apoptosis of uterine cervix cancer cells via aberrantly expressed vanilloid receptor-1. Gynecol Oncol 93(1):182–188. doi: 10.1016/j.ygyno.2003.12.040 PubMedCrossRefGoogle Scholar
  14. Costa MA, Fonseca BM, Keating E, Teixeira NA, Correia-da-Silva G (2014a) 2-Arachidonoylglycerol effects in cytotrophoblasts: metabolic enzymes expression and apoptosis in BeWo cells. Reproduction 147(3):301–311. doi: 10.1530/REP-13-0563 PubMedCrossRefGoogle Scholar
  15. Costa MA, Fonseca BM, Keating E, Teixeira NA, Correia-Da-Silva G (2014b) Transient receptor potential vanilloid 1 is expressed in human cytotrophoblasts: induction of cell apoptosis and impairment of syncytialization. Int J Biochem Cell Biol 57:177–185. doi: 10.1016/j.biocel.2014.10.008 PubMedCrossRefGoogle Scholar
  16. Costa MA, Fonseca BM, Teixeira NA, Correia-da-Silva G (2015a) The endocannabinoid anandamide induces apoptosis in cytotrophoblast cells: involvement of both mitochondrial and death receptor pathways. Placenta 36(1):69–76. doi: 10.1016/j.placenta.2014.10.011 PubMedCrossRefGoogle Scholar
  17. Costa MA, Keating E, Fonseca BM, Teixeira NA, Correia-da-Silva G (2015b) 2-Arachidonoylglycerol impairs human cytotrophoblast cells syncytialization: influence of endocannabinoid signalling in placental development. Mol Cell Endocrinol 399:386–394. doi: 10.1016/j.mce.2014.09.005 PubMedCrossRefGoogle Scholar
  18. Costa L, Amaral C, Teixeira N, Correia-da-Silva G, Fonseca BM (2016) Cannabinoid-induced autophagy: protective or death role? Prostaglandins Other Lipid Mediators 122:54–63. doi: 10.1016/j.prostaglandins.2015.12.006 PubMedCrossRefGoogle Scholar
  19. Cuervo AM, Wong E (2014) Chaperone-mediated autophagy: roles in disease and aging. Cell Res 24(1):92–104. doi: 10.1038/cr.2013.153 PubMedCrossRefGoogle Scholar
  20. De Petrocellis L, Melck D, Palmisano A, Bisogno T, Laezza C, Bifulco M, Di Marzo V (1998) The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc Natl Acad Sci U S A 95(14):8375–8380PubMedPubMedCentralCrossRefGoogle Scholar
  21. De Petrocellis L, Ligresti A, Schiano Moriello A, Iappelli M, Verde R, Stott CG, Cristino L, Orlando P, Di Marzo V (2013) Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms. Br J Pharmacol 168(1):79–102. doi: 10.1111/j.1476-5381.2012.02027.x PubMedPubMedCentralCrossRefGoogle Scholar
  22. del Pulgar T, Velasco G, Guzman M (2000) The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt. Biochem J 347:369–373CrossRefGoogle Scholar
  23. DeMorrow S, Glaser S, Francis H, Venter J, Vaculin B, Vaculin S, Alpini G (2007) Opposing actions of endocannabinoids on cholangiocarcinoma growth: recruitment of Fas and Fas ligand to lipid rafts. J Biol Chem 282(17):13098–13113. doi: 10.1074/jbc.M608238200 PubMedCrossRefGoogle Scholar
  24. Derkinderen P, Toutant M, Burgaya F, Le Bert M, Siciliano JC, de Franciscis V, Gelman M, Girault JA (1996) Regulation of a neuronal form of focal adhesion kinase by anandamide. Science 273(5282):1719–1722PubMedCrossRefGoogle Scholar
  25. Deutsch DG, Chin SA (1993) Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. Biochem Pharmacol 46(5):791–796PubMedCrossRefGoogle Scholar
  26. Devane WA, Dysarz FA III, Johnson MR, Melvin LS, Howlett AC (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34(5):605–613PubMedGoogle Scholar
  27. 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(5090):1946–1949. doi: 10.1126/science.1470919 PubMedCrossRefGoogle Scholar
  28. Di Marzo V, Despres JP (2009) CB1 antagonists for obesity – what lessons have we learned from rimonabant? Nat Rev Endocrinol 5(11):633–638. doi: 10.1038/nrendo.2009.197 PubMedCrossRefGoogle Scholar
  29. Di Marzo V, Melck D, Orlando P, Bisogno T, Zagoory O, Bifulco M, Vogel Z, De Petrocellis L (2001) Palmitoylethanolamide inhibits the expression of fatty acid amide hydrolase and enhances the anti-proliferative effect of anandamide in human breast cancer cells. Biochem J 358(Pt 1):249–255PubMedPubMedCentralCrossRefGoogle Scholar
  30. Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathuria S, Piomelli D (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci U S A 99(16):10819–10824. doi: 10.1073/pnas.152334899 PubMedPubMedCentralCrossRefGoogle Scholar
  31. Do Y, McKallip RJ, Nagarkatti M, Nagarkatti PS (2004) Activation through cannabinoid receptors 1 and 2 on dendritic cells triggers NF-kappaB-dependent apoptosis: novel role for endogenous and exogenous cannabinoids in immunoregulation. J Immunol 173(4):2373–2382PubMedCrossRefGoogle Scholar
  32. Donadelli M, Dando I, Zaniboni T, Costanzo C, Dalla Pozza E, Scupoli MT, Scarpa A, Zappavigna S, Marra M, Abbruzzese A, Bifulco M, Caraglia M, Palmieri M (2011) Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism. Cell Death Dis 2:e152. doi: 10.1038/cddis.2011.36 PubMedPubMedCentralCrossRefGoogle Scholar
  33. Eldeeb K, Leone-Kabler S, Howlett AC (2016) CB1 cannabinoid receptor-mediated increases in cyclic AMP accumulation are correlated with reduced Gi/o function. J Basic Clin Physiol Pharmacol 27(3):311–322. doi: 10.1515/jbcpp-2015-0096 PubMedCrossRefPubMedCentralGoogle Scholar
  34. Ellert-Miklaszewska A, Grajkowska W, Gabrusiewicz K, Kaminska B, Konarska L (2007) Distinctive pattern of cannabinoid receptor type II (CB2) expression in adult and pediatric brain tumors. Brain Res 1137(1):161–169. doi: 10.1016/j.brainres.2006.12.060 PubMedCrossRefGoogle Scholar
  35. Engels FK, de Jong FA, Sparreboom A, Mathot RAA, Loos WJ, Kitzen JJEM, de Bruijn P, Verweij J, Mathijssen RHJ (2007) Medicinal cannabis does not influence the clinical pharmacokinetics of irinotecan and docetaxel. Oncologist 12(3):291–300. doi: 10.1634/theoncologist.12-3-291 PubMedCrossRefGoogle Scholar
  36. 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(3):443–450PubMedGoogle Scholar
  37. Fonseca BM, Correia-da-Silva G, Taylor AH, Konje JC, Bell SC, Teixeira NA (2009a) Spatio-temporal expression patterns of anandamide-binding receptors in rat implantation sites: evidence for a role of the endocannabinoid system during the period of placental development. Reprod Biol Endocrinol 7:121. doi: 10.1186/1477-7827-7-121 PubMedPubMedCentralCrossRefGoogle Scholar
  38. Fonseca BM, Correia-da-Silva G, Teixeira NA (2009b) Anandamide-induced cell death: dual effects in primary rat decidual cell cultures. Placenta 30(8):686–692. doi: 10.1016/j.placenta.2009.05.012 PubMedCrossRefGoogle Scholar
  39. Fonseca BM, Correia-da-Silva G, Taylor AH, Lam PM, Marczylo TH, Bell SC, Konje JC, Teixeira NA (2010) The endocannabinoid 2-arachidonoylglycerol (2-AG) and metabolizing enzymes during rat fetoplacental development: a role in uterine remodelling. Int J Biochem Cell Biol 42(11):1884–1892. doi: 10.1016/j.biocel.2010.08.006 PubMedCrossRefGoogle Scholar
  40. Fonseca BM, Correia-da-Silva G, Teixeira NA (2013) The endocannabinoid anandamide induces apoptosis of rat decidual cells through a mechanism involving ceramide synthesis and p38 MAPK activation. Apoptosis 18(12):1526–1535. doi: 10.1007/s10495-013-0892-9 PubMedCrossRefGoogle Scholar
  41. Gabrielli M, Battista N, Riganti L, Prada I, Antonucci F, Cantone L, Matteoli M, Maccarrone M, Verderio C (2015) Active endocannabinoids are secreted on extracellular membrane vesicles. EMBO Rep 16(2):213–220. doi: 10.15252/embr.201439668 PubMedPubMedCentralCrossRefGoogle Scholar
  42. Galve-Roperh I, Sanchez C, Cortes ML, Gomez del Pulgar T, Izquierdo M, Guzman M (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 6(3):313–319. doi: 10.1038/73171 PubMedCrossRefGoogle Scholar
  43. Gaoni Y, Mechoulam R (1964) Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc 86(8):1646–1647. doi: 10.1021/Ja01062a046 CrossRefGoogle Scholar
  44. Gomez Del Pulgar T, De Ceballos ML, Guzman M, Velasco G (2002) Cannabinoids protect astrocytes from ceramide-induced apoptosis through the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 277(39):36527–36533. doi: 10.1074/jbc.M205797200 PubMedCrossRefGoogle Scholar
  45. Gomez R, Conde J, Scotece M, Lopez V, Lago F, Gomez Reino JJ, Gualillo O (2014) Endogenous cannabinoid anandamide impairs cell growth and induces apoptosis in chondrocytes. J Orthop Res 32(9):1137–1146. doi: 10.1002/jor.22660 PubMedCrossRefGoogle Scholar
  46. Greenhough A, Patsos HA, Williams AC, Paraskeva C (2007) The cannabinoid delta(9)-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells. Int J Cancer 121(10):2172–2180. doi: 10.1002/ijc.22917 PubMedCrossRefGoogle Scholar
  47. Guida M, Ligresti A, De Filippis D, D’Amico A, Petrosino S, Cipriano M, Bifulco G, Simonetti S, Orlando P, Insabato L, Nappi C, Di Spiezio SA, Di Marzo V, Iuvone T (2010) The levels of the endocannabinoid receptor CB2 and its ligand 2-arachidonoylglycerol are elevated in endometrial carcinoma. Endocrinology 151(3):921–928. doi: 10.1210/en.2009-0883 PubMedCrossRefGoogle Scholar
  48. Gustafsson K, Christensson B, Sander B, Flygare J (2006) Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma. Mol Pharmacol 70(5):1612–1620. doi: 10.1124/mol.106.025981 PubMedCrossRefGoogle Scholar
  49. Gustafsson SB, Lindgren T, Jonsson M, Jacobsson SO (2009) Cannabinoid receptor-independent cytotoxic effects of cannabinoids in human colorectal carcinoma cells: synergism with 5-fluorouracil. Cancer Chemother Pharmacol 63(4):691–701. doi: 10.1007/s00280-008-0788-5 PubMedCrossRefGoogle Scholar
  50. Gustafsson SB, Wallenius A, Zackrisson H, Popova D, Forshell LP, Jacobsson SOP (2013) Effects of cannabinoids and related fatty acids upon the viability of P19 embryonal carcinoma cells. Arch Toxicol 87(11):1939–1951. doi: 10.1007/s00204-013-1051-3 PubMedCrossRefGoogle Scholar
  51. Guzman M, Duarte MJ, Blazquez C, Ravina J, Rosa MC, Galve-Roperh I, Sanchez C, Velasco G, Gonzalez-Feria L (2006) A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer 95(2):197–203. doi: 10.1038/sj.bjc.6603236 PubMedPubMedCentralCrossRefGoogle Scholar
  52. Herrera B, Carracedo A, Diez-Zaera M, Gomez del Pulgar T, Guzman M, Velasco G (2006) The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway. Exp Cell Res 312(11):2121–2131. doi: 10.1016/j.yexcr.2006.03.009 PubMedCrossRefGoogle Scholar
  53. Higgs HN, Glomset JA (1994) Identification of a phosphatidic acid-preferring phospholipase A1 from bovine brain and testis. Proc Natl Acad Sci U S A 91(20):9574–9578PubMedPubMedCentralCrossRefGoogle Scholar
  54. Hinz B, Ramer R, Eichele K, Weinzierl U, Brune K (2004a) R(+)-methanandamide-induced cyclooxygenase-2 expression in H4 human neuroglioma cells: possible involvement of membrane lipid rafts. Biochem Biophys Res Commun 324(2):621–626. doi: 10.1016/j.bbrc.2004.09.095 PubMedCrossRefGoogle Scholar
  55. Hinz B, Ramer R, Eichele K, Weinzierl U, Brune K (2004b) Up-regulation of cyclooxygenase-2 expression is involved in R(+)-methanandamide-induced apoptotic death of human neuroglioma cells. Mol Pharmacol 66(6):1643–1651. doi: 10.1124/mol.104.002618 PubMedCrossRefGoogle Scholar
  56. Hong Y, Zhou Y, Wang Y, Xiao S, Liao DJ, Zhao Q (2013) PPARgamma mediates the effects of WIN55,212-2, an synthetic cannabinoid, on the proliferation and apoptosis of the BEL-7402 hepatocarcinoma cells. Mol Biol Rep 40(11):6287–6293. doi: 10.1007/s11033-013-2741-x PubMedCrossRefGoogle Scholar
  57. Hsu SS, Huang CJ, Cheng HH, Chou CT, Lee HY, Wang JL, Chen IS, Liu SI, Lu YC, Chang HT, Huang JK, Chen JS, Jan CR (2007) Anandamide-induced Ca2+ elevation leading to p38 MAPK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells. Toxicology 231(1):21–29. doi: 10.1016/j.tox.2006.11.005 PubMedCrossRefGoogle Scholar
  58. Izzo AA, Aviello G, Petrosino S, Orlando P, Marsicano G, Lutz B, Borrelli F, Capasso R, Nigam S, Capasso F, Di Marzo V, Endocannabinoid Research G (2008) Increased endocannabinoid levels reduce the development of precancerous lesions in the mouse colon. J Mol Med 86(1):89–98. doi: 10.1007/s00109-007-0248-4 PubMedCrossRefGoogle Scholar
  59. Jia W, Hegde VL, Singh NP, Sisco D, Grant S, Nagarkatti M, Nagarkatti PS (2006) Delta9-tetrahydrocannabinol-induced apoptosis in Jurkat leukemia T cells is regulated by translocation of bad to mitochondria. Mol Cancer Res 4(8):549–562. doi: 10.1158/1541-7786.MCR-05-0193 PubMedCrossRefGoogle Scholar
  60. Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT (2010) Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manag 39(2):167–179. doi: 10.1016/j.jpainsymman.2009.06.008 CrossRefGoogle Scholar
  61. Kano M (2014) Control of synaptic function by endocannabinoid-mediated retrograde signaling. Proc Jpn Acad Ser B Phys Biol Sci 90(7):235–250PubMedPubMedCentralCrossRefGoogle Scholar
  62. Kaur J, Debnath J (2015) Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol 16(8):461–472. doi: 10.1038/nrm4024 PubMedCrossRefGoogle Scholar
  63. Kerbrat A, Ferre JC, Fillatre P, Ronziere T, Vannier S, Carsin-Nicol B, Lavoue S, Verin M, Gauvrit JY, Le Tulzo Y, Edan G (2016) Acute neurologic disorder from an inhibitor of fatty acid amide hydrolase. N Engl J Med 375(18):1717–1725. doi: 10.1056/NEJMoa1604221 PubMedCrossRefGoogle Scholar
  64. Kim SR, Lee DY, Chung ES, Oh UT, Kim SU, Jin BK (2005) Transient receptor potential vanilloid subtype 1 mediates cell death of mesencephalic dopaminergic neurons in vivo and in vitro. J Neurosci 25(3):662–671. doi: 10.1523/JNEUROSCI.4166-04.2005 PubMedCrossRefGoogle Scholar
  65. Koay LC, Rigby RJ, Wright KL (2014) Cannabinoid-induced autophagy regulates suppressor of cytokine signaling-3 in intestinal epithelium. Am J Physiol Gastrointest Liver Physiol 307(2):G140–G148. doi: 10.1152/ajpgi.00317.2013 PubMedPubMedCentralCrossRefGoogle Scholar
  66. Laezza C, Pisanti S, Malfitano AM, Bifulco M (2008) The anandamide analog, Met-F-AEA, controls human breast cancer cell migration via the RHOA/RHO kinase signaling pathway. Endocr Relat Cancer 15(4):965–974. doi: 10.1677/ERC-08-0030 PubMedCrossRefGoogle Scholar
  67. Lauckner JE, Hille B, Mackie K (2005) The cannabinoid agonist WIN55,212-2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins. Proc Natl Acad Sci U S A 102(52):19144–19149. doi: 10.1073/pnas.0509588102 PubMedPubMedCentralCrossRefGoogle Scholar
  68. Ligresti A, Bisogno T, Matias I, De Petrocellis L, Cascio MG, Cosenza V, D’Argenio G, Scaglione G, Bifulco M, Sorrentini I, Di Marzo V (2003) Possible endocannabinoid control of colorectal cancer growth. Gastroenterology 125(3):677–687PubMedCrossRefGoogle Scholar
  69. Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, Laezza C, Portella G, Bifulco M, Di Marzo V (2006) Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 318(3):1375–1387. doi: 10.1124/jpet.106.105247 PubMedCrossRefGoogle Scholar
  70. Ligresti A, De Petrocellis L, Di Marzo V (2016) From phytocannabinoids to cannabinoid receptors and endocannabinoids: pleiotropic physiological and pathological roles through complex pharmacology. Physiol Rev 96(4):1593–1659. doi: 10.1152/physrev.00002.2016 PubMedCrossRefGoogle Scholar
  71. Lim MP, Devi LA, Rozenfeld R (2011) Cannabidiol causes activated hepatic stellate cell death through a mechanism of endoplasmic reticulum stress-induced apoptosis. Cell Death Dis 2:e170. doi: 10.1038/cddis.2011.52 PubMedPubMedCentralCrossRefGoogle Scholar
  72. Liu J, Wang L, Harvey-White J, Osei-Hyiaman D, Razdan R, Gong Q, Chan AC, Zhou Z, Huang BX, Kim HY, Kunos G (2006) A biosynthetic pathway for anandamide. Proc Natl Acad Sci U S A 103(36):13345–13350. doi: 10.1073/pnas.0601832103 PubMedPubMedCentralCrossRefGoogle Scholar
  73. Liu J, Wang L, Harvey-White J, Huang BX, Kim HY, Luquet S, Palmiter RD, Krystal G, Rai R, Mahadevan A, Razdan RK, Kunos G (2008) Multiple pathways involved in the biosynthesis of anandamide. Neuropharmacology 54(1):1–7. doi: 10.1016/j.neuropharm.2007.05.020 PubMedCrossRefGoogle Scholar
  74. Lograno MD, Romano MR (2004) Cannabinoid agonists induce contractile responses through G(i/o)-dependent activation of phospholipase C in the bovine ciliary muscle. Eur J Pharmacol 494(1):55–62. doi: 10.1016/j.ejphar.2004.04.039 PubMedCrossRefGoogle Scholar
  75. Lonardi S, Tosoni A, Brandes AA (2005) Adjuvant chemotherapy in the treatment of high grade gliomas. Cancer Treat Rev 31(2):79–89. doi: 10.1016/j.ctrv.2004.12.005 PubMedCrossRefGoogle Scholar
  76. Lorente M, Carracedo A, Torres S, Natali F, Egia A, Hernandez-Tiedra S, Salazar M, Blazquez C, Guzman M, Velasco G (2009) Amphiregulin is a factor for resistance of glioma cells to cannabinoid-induced apoptosis. Glia 57(13):1374–1385. doi: 10.1002/glia.20856 PubMedCrossRefGoogle Scholar
  77. Lorente M, Torres S, Salazar M, Carracedo A, Hernandez-Tiedra S, Rodriguez-Fornes F, Garcia-Taboada E, Melendez B, Mollejo M, Campos-Martin Y, Lakatosh SA, Barcia J, Guzman M, Velasco G (2011) Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action. Cell Death Differ 18(6):959–973. doi: 10.1038/cdd.2010.170 PubMedPubMedCentralCrossRefGoogle Scholar
  78. Maccarrone M, Lorenzon T, Bari M, Melino G, Finazzi-Agro A (2000) Anandamide induces apoptosis in human cells via vanilloid receptors – evidence for a protective role of cannabinoid receptors. J Biol Chem 275(41):31938–31945. doi: 10.1074/jbc.M005722200 PubMedCrossRefGoogle Scholar
  79. Mackie K, Lai Y, Westenbroek R, Mitchell R (1995) Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. J Neurosci 15(10):6552–6561PubMedGoogle Scholar
  80. 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(6284):561–564. doi: 10.1038/346561a0 PubMedCrossRefGoogle Scholar
  81. May MB, Glode AE (2016) Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics. Cancer Manag Res 8:49–55. doi: 10.2147/CMAR.S81425 PubMedPubMedCentralGoogle Scholar
  82. Mechoulam R, Benshabat 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(1):83–90. doi: 10.1016/0006-2952(95)00109-D PubMedCrossRefGoogle Scholar
  83. Mechoulam R, Hanus LO, Pertwee R, Howlett AC (2014) Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat Rev Neurosci 15(11):757–764. doi: 10.1038/nrn3811 PubMedCrossRefGoogle Scholar
  84. Melck D, Rueda D, Galve-Roperh I, De Petrocellis L, Guzman M, Di Marzo V (1999) Involvement of the cAMP/protein kinase A pathway and of mitogen-activated protein kinase in the anti-proliferative effects of anandamide in human breast cancer cells. FEBS Lett 463(3):235–240PubMedCrossRefGoogle Scholar
  85. Melck D, De Petrocellis L, Orlando P, Bisogno T, Laezza C, Bifulco M, Di Marzo V (2000) Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. Endocrinology 141(1):118–126. doi: 10.1210/endo.141.1.7239 PubMedCrossRefGoogle Scholar
  86. Miyato H, Kitayama J, Yamashita H, Souma D, Asakage M, Yamada J, Nagawa H (2009) Pharmacological synergism between cannabinoids and paclitaxel in gastric cancer cell lines. J Surg Res 155(1):40–47. doi: 10.1016/j.jss.2008.06.045 PubMedCrossRefGoogle Scholar
  87. Movsesyan VA, Stoica BA, Yakovlev AG, Knoblach SM, Lea PM, Cernak I, Vink R, Faden AI (2004) Anandamide-induced cell death in primary neuronal cultures: role of calpain and caspase pathways. Cell Death Differ 11(10):1121–1132. doi: 10.1038/sj.cdd.4401442 PubMedCrossRefGoogle Scholar
  88. Muccioli GG (2010) Endocannabinoid biosynthesis and inactivation, from simple to complex. Drug Discov Today 15(11–12):474–483. doi: 10.1016/j.drudis.2010.03.007 PubMedCrossRefGoogle Scholar
  89. Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365(6441):61–65. doi: 10.1038/365061a0 PubMedCrossRefGoogle Scholar
  90. Munson AE, Harris LS, Friedman MA, Dewey WL, Carchman RA (1975) Antineoplastic activity of cannabinoids. J Natl Cancer Inst 55(3):597–602PubMedCrossRefGoogle Scholar
  91. Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y (2009) Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10(7):458–467. doi: 10.1038/nrm2708 PubMedCrossRefGoogle Scholar
  92. Notaro A, Sabella S, Pellerito O, Di Fiore R, De Blasio A, Vento R, Calvaruso G, Giuliano M (2014) Involvement of PAR-4 in cannabinoid-dependent sensitization of osteosarcoma cells to TRAIL-induced apoptosis. Int J Biol Sci 10(5):466–478. doi: 10.7150/ijbs.8337 PubMedPubMedCentralCrossRefGoogle Scholar
  93. O’Sullivan SE (2007) Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol 152(5):576–582. doi: 10.1038/sj.bjp.0707423 PubMedPubMedCentralCrossRefGoogle Scholar
  94. Orellana-Serradell O, Poblete CE, Sanchez C, Castellon EA, Gallegos I, Huidobro C, Llanos MN, Contreras HR (2015) Proapoptotic effect of endocannabinoids in prostate cancer cells. Oncol Rep 33(4):1599–1608. doi: 10.3892/or.2015.3746 PubMedPubMedCentralGoogle Scholar
  95. Pagano E, Borrelli F, Orlando P, Romano B, Monti M, Morbidelli L, Aviello G, Imperatore R, Capasso R, Piscitelli F, Buono L, Di Marzo V, Izzo AA (2017) Pharmacological inhibition of MAGL attenuates experimental colon carcinogenesis. Pharmacol Res 119:227–236. doi: 10.1016/j.phrs.2017.02.002 PubMedCrossRefGoogle Scholar
  96. Pan X, Ikeda SR, Lewis DL (1996) Rat brain cannabinoid receptor modulates N-type Ca2+ channels in a neuronal expression system. Mol Pharmacol 49(4):707–714PubMedGoogle Scholar
  97. Patsos HA, Greenhough A, Hicks DJ, Al Kharusi M, Collard TJ, Lane JD, Paraskeva C, Williams AC (2010) The endogenous cannabinoid, anandamide, induces COX-2-dependent cell death in apoptosis-resistant colon cancer cells. Int J Oncol 37(1):187–193. doi: 10.3892/ijo_00000666 PubMedGoogle Scholar
  98. Pellerito O, Notaro A, Sabella S, De Blasio A, Vento R, Calvaruso G, Giuliano M (2014) WIN induces apoptotic cell death in human colon cancer cells through a block of autophagic flux dependent on PPAR gamma down-regulation. Apoptosis 19(6):1029–1042. doi: 10.1007/s10495-014-0985-0 PubMedGoogle Scholar
  99. Pertwee RG (2000) Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development. Expert Opin Investig Drugs 9(7):1553–1571. doi: 10.1517/13543784.9.7.1553 PubMedCrossRefGoogle Scholar
  100. Pozzoli G, Tringali G, Vairano M, D’Amico M, Navarra P, Martire M (2006) Cannabinoid agonist WIN55,212-2 induces apoptosis in cerebellar granule cells via activation of the CB1 receptor and downregulation of bcl-xL gene expression. J Neurosci Res 83(6):1058–1065. doi: 10.1002/jnr.20794 PubMedCrossRefGoogle Scholar
  101. Preet A, Qamri Z, Nasser MW, Prasad A, Shilo K, Zou X, Groopman JE, Ganju RK (2011) Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis. Cancer Prev Res 4(1):65–75. doi: 10.1158/1940-6207.CAPR-10-0181 CrossRefGoogle Scholar
  102. Pucci M, Pasquariello N, Battista N, Di Tommaso M, Rapino C, Fezza F, Zuccolo M, Jourdain R, Agro AF, Breton L, Maccarrone M (2012) Endocannabinoids stimulate human melanogenesis via type-1 cannabinoid receptor. J Biol Chem 287(19):15466–15478. doi: 10.1074/jbc.M111.314880 PubMedPubMedCentralCrossRefGoogle Scholar
  103. Rajesh M, Mukhopadhyay P, Hasko G, Liaudet L, Mackie K, Pacher P (2010) Cannabinoid-1 receptor activation induces reactive oxygen species-dependent and -independent mitogen-activated protein kinase activation and cell death in human coronary artery endothelial cells. Br J Pharmacol 160(3):688–700. doi: 10.1111/j.1476-5381.2010.00712.x PubMedPubMedCentralCrossRefGoogle Scholar
  104. Ramer R, Hinz B (2008) Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1. J Natl Cancer Inst 100(1):59–69. doi: 10.1093/jnci/djm268 PubMedCrossRefGoogle Scholar
  105. Ramer R, Heinemann K, Merkord J, Rohde H, Salamon A, Linnebacher M, Hinz B (2013) COX-2 and PPAR-gamma confer cannabidiol-induced apoptosis of human lung cancer cells. Mol Cancer Ther 12(1):69–82. doi: 10.1158/1535-7163.MCT-12-0335 PubMedCrossRefGoogle Scholar
  106. 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 gamma independently of cannabinoid receptors 1 and 2. Mol Pharmacol 70(1):101–111. doi: 10.1124/mol.105.019117 PubMedGoogle Scholar
  107. Rockwell CE, Raman P, Kaplan BLF, Kaminski NE (2008) A COX-2 metabolite of the endogenous cannabinoid, 2-arachidonyl glycerol, mediates suppression of IL-2 secretion in activated Jurkat T cells. Biochem Pharmacol 76(3):353–361. doi: 10.1016/j.bcp.2008.05.005 PubMedCrossRefGoogle Scholar
  108. Ruiz L, Miguel A, Diaz-Laviada I (1999) Delta9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism. FEBS Lett 458(3):400–404PubMedCrossRefGoogle Scholar
  109. Salazar M, Carracedo A, Salanueva IJ, Hernandez-Tiedra S, Lorente M, Egia A, Vazquez P, Blazquez C, Torres S, Garcia S, Nowak J, Fimia GM, Piacentini M, Cecconi F, Pandolfi PP, Gonzalez-Feria L, Iovanna JL, Guzman M, Boya P, Velasco G (2009) Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest 119(5):1359–1372PubMedPubMedCentralCrossRefGoogle Scholar
  110. Sanchez C, Galve-Roperh I, Canova C, Brachet P, Guzman M (1998) Delta9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Lett 436(1):6–10PubMedCrossRefGoogle Scholar
  111. Sanchez C, de Ceballos ML, Gomez del Pulgar T, Rueda D, Corbacho C, Velasco G, Galve-Roperh I, Huffman JW, Ramon y Cajal S, Guzman M (2001a) Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res 61(15):5784–5789PubMedGoogle Scholar
  112. Sanchez C, Rueda D, Segui B, Galve-Roperh I, Levade T, Guzman M (2001b) The CB1 cannabinoid receptor of astrocytes is coupled to sphingomyelin hydrolysis through the adaptor protein fan. Mol Pharmacol 59(5):955–959PubMedGoogle Scholar
  113. Sanchez MG, Ruiz-Llorente L, Sanchez AM, Diaz-Laviada I (2003) Activation of phosphoinositide 3-kinase/PKB pathway by CB1 and CB2 cannabinoid receptors expressed in prostate PC-3 cells. Involvement in Raf-1 stimulation and NGF induction. Cell Signal 15(9):851–859. doi: 10.1016/S0898-6568(03)00036-6 PubMedCrossRefGoogle Scholar
  114. Sarker KP, Maruyama I (2003) Anandamide induces cell death independently of cannabinoid receptors or vanilloid receptor 1: possible involvement of lipid rafts. Cell Mol Life Sci 60(6):1200–1208. doi: 10.1007/s00018-003-3055-2 PubMedCrossRefGoogle Scholar
  115. Sarker KP, Obara S, Nakata M, Kitajima I, Maruyama I (2000) Anandamide induces apoptosis of PC-12 cells: involvement of superoxide and caspase-3. FEBS Lett 472(1):39–44PubMedCrossRefGoogle Scholar
  116. Shao Z, Yin J, Chapman K, Grzemska M, Clark L, Wang J, Rosenbaum DM (2016) High-resolution crystal structure of the human CB1 cannabinoid receptor. Nature 540:602–606. doi: 10.1038/nature20613 CrossRefGoogle Scholar
  117. Shrivastava A, Kuzontkoski PM, Groopman JE, Prasad A (2011) Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. Mol Cancer Ther 10(7):1161–1172. doi: 10.1158/1535-7163.MCT-10-1100 PubMedCrossRefGoogle Scholar
  118. Simon GM, Cravatt BF (2006) Endocannabinoid biosynthesis proceeding through glycerophospho-N-acyl ethanolamine and a role for alpha/beta-hydrolase 4 in this pathway. J Biol Chem 281(36):26465–26472. doi: 10.1074/jbc.M604660200 PubMedCrossRefGoogle Scholar
  119. Skaper SD, Buriani A, Dal Toso R, Petrelli L, Romanello S, Facci L, Leon A (1996) The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. Proc Natl Acad Sci U S A 93(9):3984–3989PubMedPubMedCentralCrossRefGoogle Scholar
  120. Snider NT, Sikora MJ, Sridar C, Feuerstein TJ, Rae JM, Hollenberg PF (2008) The endocannabinoid anandamide is a substrate for the human polymorphic cytochrome P450 2D6. J Pharmacol Exp Ther 327(2):538–545. doi: 10.1124/jpet.108.141796 PubMedPubMedCentralCrossRefGoogle Scholar
  121. Strasser F, Luftner D, Possinger K, Ernst G, Ruhstaller T, Meissner W, Ko YD, Schnelle M, Reif M, Cerny T (2006) Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol Off J Am Soc Clin Oncol 24(21):3394–3400. doi: 10.1200/JCO.2005.05.1847 CrossRefGoogle Scholar
  122. Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, Han W, Lou F, Yang J, Zhang Q, Wang X, He C, Pan H (2013) Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis 4:e838. doi: 10.1038/cddis.2013.350 PubMedPubMedCentralCrossRefGoogle Scholar
  123. Svizenska I, Dubovy P, Sulcova A (2008) Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures – a short review. Pharmacol Biochem Behav 90(4):501–511. doi: 10.1016/j.pbb.2008.05.010 PubMedCrossRefGoogle Scholar
  124. Torres S, Lorente M, Rodriguez-Fornes F, Hernandez-Tiedra S, Salazar M, Garcia-Taboada E, Barcia J, Guzman M, Velasco G (2011) A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther 10(1):90–103. doi: 10.1158/1535-7163.MCT-10-0688 PubMedCrossRefGoogle Scholar
  125. Van Dross RT (2009) Metabolism of anandamide by COX-2 is necessary for endocannabinoid-induced cell death in tumorigenic keratinocytes. Mol Carcinog 48(8):724–732. doi: 10.1002/mc.20515 PubMedCrossRefGoogle Scholar
  126. Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison JS, Marnett LJ, Di Marzo V, Pittman QJ, Patel KD, Sharkey KA (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310(5746):329–332. doi: 10.1126/science.1115740 PubMedCrossRefGoogle Scholar
  127. Vara D, Morell C, Rodriguez-Henche N, Diaz-Laviada I (2013) Involvement of PPAR gamma in the antitumoral action of cannabinoids on hepatocellular carcinoma. Cell Death Dis 4:e618. doi: 10.1038/cddis.2013.141 PubMedPubMedCentralCrossRefGoogle Scholar
  128. Velasco G, Galve-Roperh I, Sanchez C, Blazquez C, Haro A, Guzman M (2005) Cannabinoids and ceramide: two lipids acting hand-by-hand. Life Sci 77(14):1723–1731. doi: 10.1016/j.lfs.2005.05.015 PubMedCrossRefGoogle Scholar
  129. Velasco G, Sanchez C, Guzman M (2016) Anticancer mechanisms of cannabinoids. Curr Oncol 23(2):S23–S32. doi: 10.3747/co.23.3080 PubMedPubMedCentralGoogle Scholar
  130. Wade MR, Tzavara ET, Nomikos GG (2004) Cannabinoids reduce cAMP levels in the striatum of freely moving rats: an in vivo microdialysis study. Brain Res 1005(1–2):117–123. doi: 10.1016/j.brainres.2004.01.039 PubMedCrossRefGoogle Scholar
  131. Wu HY, Chang AC, Wang CC, Kuo FH, Lee CY, Liu DZ, Jan TR (2010) Cannabidiol induced a contrasting pro-apoptotic effect between freshly isolated and precultured human monocytes. Toxicol Appl Pharmacol 246(3):141–147. doi: 10.1016/j.taap.2010.05.003 PubMedCrossRefGoogle Scholar
  132. Wu HY, Goble K, Mecha M, Wang CC, Huang CH, Guaza C, Jan TR (2012) Cannabidiol-induced apoptosis in murine microglial cells through lipid raft. Glia 60(7):1182–1190. doi: 10.1002/glia.22345 PubMedCrossRefGoogle Scholar
  133. Xu Y, Wang C, Li Z (2014) A new strategy of promoting cisplatin chemotherapeutic efficiency by targeting endoplasmic reticulum stress. Mol Clin Oncol 2(1):3–7. doi: 10.3892/mco.2013.202 PubMedGoogle Scholar
  134. Yamaori S, Ishii H, Chiba K, Yamamoto I, Watanabe K (2013) Delta-tetrahydrocannabinol induces cytotoxicity in macrophage J774-1 cells: involvement of cannabinoid receptor 2 and p38 MAPK. Toxicology 314(2–3):254–261. doi: 10.1016/j.tox.2013.10.007 PubMedCrossRefGoogle Scholar
  135. Zoratti C, Kipmen-Korgun D, Osibow K, Malli R, Graier WF (2003) Anandamide initiates Ca(2+) signaling via CB2 receptor linked to phospholipase C in calf pulmonary endothelial cells. Br J Pharmacol 140(8):1351–1362. doi: 10.1038/sj.bjp.0705529 PubMedPubMedCentralCrossRefGoogle Scholar
  136. Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D, Hogestatt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400(6743):452–457. doi: 10.1038/22761 PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • B. M. Fonseca
    • 1
  • N. A. Teixeira
    • 1
  • G. Correia-da-Silva
    • 1
  1. 1.UCIBIO, REQUIMTE, Laboratório de Bioquímica, Departamento Ciências BiológicasFaculdade de Farmácia da Universidade do PortoPortoPortugal

Personalised recommendations