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Cannabinoid Receptors in Regulating the GI Tract: Experimental Evidence and Therapeutic Relevance

Part of the Handbook of Experimental Pharmacology book series (HEP,volume 239)

Abstract

Cannabinoid receptors are fundamentally involved in all aspects of intestinal physiology, such as motility, secretion, and epithelial barrier function. They are part of a broader entity, the so-called endocannabinoid system which also includes their endocannabinoid ligands and the ligands’ synthesizing/degrading enzymes. The system has a strong impact on the pathophysiology of the gastrointestinal tract and is believed to maintain homeostasis in the gut by controlling hypercontractility and by promoting regeneration after injury. For instance, genetic knockout of cannabinoid receptor 1 leads to inflammation and cancer of the intestines. Derivatives of Δ9-tetrahydrocannabinol, such as nabilone and dronabinol, activate cannabinoid receptors and have been introduced into the clinic to treat chemotherapy-induced emesis and loss of appetite; however, they may cause many psychotropic side effects. New drugs that interfere with endocannabinoid degradation to raise endocannabinoid levels circumvent this obstacle and could be used in the future to treat emesis, intestinal inflammation, and functional disorders associated with visceral hyperalgesia.

Keywords

  • Cannabinoid receptors
  • Colon cancer
  • GPR55
  • IBD
  • IBS
  • Intestinal inflammation
  • PPARα
  • TRPV1

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Abbreviations

2-AG:

2-Arachidonoyl glycerol

Δ9-THC:

Δ9-Tetrahydrocannabinol

AA:

Arachidonic acid

ACEA:

Arachidonyl-2′-chloroethylamide

ACF:

Aberrant crypt foci

AEA:

Arachidonoyl ethanolamine

CB:

Cannabinoid

CBD:

Cannabidiol

CD:

Crohn’s disease

CNS:

Central nervous system

CRC:

Colorectal cancer

DAGL:

Diglyceride-specific lipase

DG:

Diglyceride

ENS:

Enteric nervous system

FAAH:

Fatty acid amide hydrolase

GI:

Gastrointestinal

GPR55:

G protein-coupled receptor 55

IBD:

Inflammatory bowel disease

IBS:

Irritable bowel syndrome

MGL:

Monoglyceride lipase

NANC:

Non-adrenergic non-cholinergic

NAPE:

N-Arachidonoyl phosphatidylethanolamine

NAPE-PLD:

NAPE-selective phospholipase D

OEA:

Oleoylethanolamide

PEA:

Palmitoylethanolamide

PPAR:

Peroxisome proliferative activated receptor

TLESR:

Transient lower esophageal sphincter relaxation

TNFα:

Tumor necrosis factor alpha

TRPV1:

Transient receptor potential cation channel subfamily V member 1

UC:

Ulcerative colitis

References

  • Abalo R, Cabezos PA, López-Miranda V et al (2009) Selective lack of tolerance to delayed gastric emptying after daily administration of WIN 55,212-2 in the rat. Neurogastroenterol Motil 21:22–24

    CrossRef  CAS  Google Scholar 

  • Adami M, Frati P, Bertini S et al (2002) Gastric antisecretory role and immunohistochemical localization of cannabinoid receptors in the rat stomach. Br J Pharmacol 135:1598–1606

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Aguilera M, Cerdà-Cuéllar M, Martínez V (2015) Antibiotic-induced dysbiosis alters host-bacterial interactions and leads to colonic sensory and motor changes in mice. Gut Microbes 6:10–23

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Alhouayek M, Muccioli GG (2012) The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity. Trends Mol Med 18:615–625

    CAS  PubMed  CrossRef  Google Scholar 

  • Ameloot K, Janssen P, Scarpellini E et al (2010) Endocannabinoid control of gastric sensorimotor function in man. Aliment Pharmacol Ther 31:1123–1131

    CAS  PubMed  Google Scholar 

  • Baldassano S, Zizzo MG, Serio R, Mulè F (2009) Interaction between cannabinoid CB 1 receptors and endogenous ATP in the control of spontaneous mechanical activity in mouse ileum. Br J Pharmacol 158:243–251

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Bashashati M, Storr MA, Nikas SP et al (2012) Inhibiting fatty acid amide hydrolase normalizes endotoxin-induced enhanced gastrointestinal motility in mice. Br J Pharmacol 165:1556–1571

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Bashashati M, Nasser Y, Keenan C et al (2015) Inhibiting endocannabinoid biosynthesis: a novel approach to the treatment of constipation. Br J Pharmacol 172:3099–3111

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Beaumont H, Jensen J, Carlsson A et al (2009) Effect of delta9-tetrahydrocannabinol, a cannabinoid receptor agonist, on the triggering of transient lower oesophageal sphincter relaxations in dogs and humans. Br J Pharmacol 156:153–162

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Bedoya F, Rubio JC, Morales-Gutierrez C et al (2009) Single nucleotide change in the cannabinoid receptor-1 (CNR1) gene in colorectal cancer outcome. Oncology 76:435–441

    CAS  PubMed  CrossRef  Google Scholar 

  • Begg M, Molleman A, Parsons M (2002) Modulation of the release of endogenous gamma-aminobutyric acid by cannabinoids in the guinea pig ileum. Eur J Pharmacol 434:87–94

    CAS  PubMed  CrossRef  Google Scholar 

  • Bisogno T, Howell F, Williams G et al (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol 163:463–468

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Boesmans W, Ameloot K, van den Abbeel V et al (2009) Cannabinoid receptor 1 signalling dampens activity and mitochondrial transport in networks of enteric neurones. Neurogastroenterol Motil 21:958 e77

    CAS  PubMed  CrossRef  Google Scholar 

  • Borrelli F (2007) Cannabinoid CB(1) receptor and gastric acid secretion. Dig Dis Sci 52:3102–3103

    PubMed  CrossRef  Google Scholar 

  • Borrelli F, Izzo AA (2009) Role of acylethanolamides in the gastrointestinal tract with special reference to food intake and energy balance. Best Pract Res Clin Endocrinol Metab 23:33–49

    CAS  PubMed  CrossRef  Google Scholar 

  • Brusberg M, Arvidsson S, Kang D et al (2009) CB1 receptors mediate the analgesic effects of cannabinoids on colorectal distension-induced visceral pain in rodents. J Neurosci 29:1554–1564

    CAS  PubMed  CrossRef  Google Scholar 

  • Buggy DJ, Toogood L, Maric S et al (2003) Lack ofanalgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain 106:169–172

    CAS  PubMed  CrossRef  Google Scholar 

  • Camilleri M (2008) Novel pharmacology: asimadoline, a kappa-opioid agonist, and visceral sensation. Neurogastroenterol Motil 20:971–979

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Camilleri M, Kolar GJ, Vazquez-Roque MI et al (2013) Cannabinoid receptor 1 gene and irritable bowel syndrome: phenotype and quantitative traits. Am J Physiol Gastrointest Liver Physiol 304:G553–G560

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Cani PD, Plovier H, Van Hul M et al (2016) Endocannabinoids – at the crossroads between the gut microbiota and host metabolism. Nat Rev Endocrinol 12:133–143

    CAS  PubMed  CrossRef  Google Scholar 

  • Capasso R, Izzo AA, Fezza F et al (2001) Inhibitory effect of palmitoylethanolamide on gastrointestinal motility in mice. Br J Pharmacol 134:945–950

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Capasso R, Matias I, Lutz B et al (2005) Fatty acid amide hydrolase controls mouse intestinal motility in vivo. Gastroenterology 129:941–951

    CAS  PubMed  CrossRef  Google Scholar 

  • Capasso R, Borrelli F, Aviello G et al (2008a) Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice. Br J Pharmacol 154:1001–1008

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Capasso R, Borrelli F, Cascio MG et al (2008b) Inhibitory effect of salvinorin A, from Salvia divinorum, on ileitis-induced hypermotility: cross-talk between kappa-opioid and cannabinoid CB(1) receptors. Br J Pharmacol 155:681–689

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Capasso R, Orlando P, Pagano E et al (2014) Palmitoylethanolamide normalizes intestinal motility in a model of post-inflammatory accelerated transit: involvement of CB1 receptors and TRPV1 channels. Br J Pharmacol 171:4026–4037

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Carai MAM, Colombo G, Gessa GL (2004) Rapid tolerance to the intestinal prokinetic effect of cannabinoid CB 1 receptor antagonist, SR 141716 (Rimonabant). Eur J Pharmacol 494:221–224

    CAS  PubMed  CrossRef  Google Scholar 

  • Chey WY, Jin HO, Lee MH et al (2001) Colonic motility abnormality in patients with irritable bowel syndrome exhibiting abdominal pain and diarrhea. Am J Gastroenterol 96:1499–1506

    CAS  PubMed  CrossRef  Google Scholar 

  • Cianchi F, Papucci L, Schiavone N et al (2008) Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha-mediated ceramide de novo synthesis in colon cancer cells. Clin Cancer Res 14:7691–7700

    CAS  PubMed  CrossRef  Google Scholar 

  • Cluny NL, Keenan CM, Lutz B et al (2009) The identification of peroxisome proliferator-activated receptor alpha-independent effects of oleoylethanolamide on intestinal transit in mice. Neurogastroenterol Motil 21:420–429

    CAS  PubMed  CrossRef  Google Scholar 

  • Coruzzi G, Adami M, Guaita E et al (2006) Effects of cannabinoid receptor agonists on rat gastric acid secretion: discrepancy between in vitro and in vivo data. Dig Dis Sci 51:310–317

    CAS  PubMed  CrossRef  Google Scholar 

  • Cota D, Marsicano G, Tschop M et al (2003) The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 112:423–431

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Coutts AA, Izzo AA (2004) The gastrointestinal pharmacology of cannabinoids: an update. Curr Opin Pharmacol 4:572–579

    CAS  PubMed  CrossRef  Google Scholar 

  • Croci T, Manara L, Aureggi G et al (1998) In vitro functional evidence of neuronal cannabinoid CB 1 receptors in human ileum. Br J Pharmacol 125:1393–1395

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Cross-Mellor SK, Ossenkopp KP, Piomelli D et al (2007) Effects of the FAAH inhibitor, URB597, and anandamide on lithium-induced taste reactivity responses: a measure of nausea in the rat. Psychopharmacology (Berl) 190:135–143

    CAS  CrossRef  Google Scholar 

  • D’Argenio G, Valenti M, Scaglione G et al (2006) Up-regulation of anandamide levels as an endogenous mechanism and a pharmacological strategy to limit colon inflammation. FASEB J 20:568–570

    PubMed  Google Scholar 

  • Deutsch DG, Chin SA (1993) Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. Biochem Pharmacol 46:791–796

    CAS  PubMed  CrossRef  Google Scholar 

  • Devane WA, Hanus L, Breuer A et al (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949

    CAS  PubMed  CrossRef  Google Scholar 

  • Dinh TP, Carpenter D, Leslie FM et al (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci U S A 99:10819–10824

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Duncan M, Davison JS, Sharkey KA (2005) Review article: endocannabinoids and their receptors in the enteric nervous system. Aliment Pharmacol Ther 22:667–683

    CAS  PubMed  CrossRef  Google Scholar 

  • Duncan M, Mouihate A, Mackie K et al (2008a) Cannabinoid CB2 receptors in the enteric nervous system modulate gastrointestinal contractility in lipopolysaccharide-treated rats. Am J Physiol Gastrointest Liver Physiol 295:G78–G87

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Duncan M, Thomas AD, Cluny NL et al (2008b) Distribution and function of monoacylglycerol lipase in the gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol 295:G1255–G1265

    CAS  PubMed  CrossRef  Google Scholar 

  • Engel MA, Kellermann CA, Burnat G et al (2010) Mice lacking cannabinoid CB1-, CB2-receptors or both receptors show increased susceptibility to trinitrobenzene sulfonic acid (TNBS)-induced colitis. J Physiol Pharmacol 61:89–97

    CAS  PubMed  Google Scholar 

  • Esfandyari T, Camilleri M, Ferber I et al (2006) Effect of a cannabinoid agonist on gastrointestinal transit and postprandial satiation in healthy human subjects: a randomized, placebo-controlled study. Neurogastroenterol Motil 18:831–838

    CAS  PubMed  CrossRef  Google Scholar 

  • Esfandyari T, Camilleri M, Busciglio I et al (2007) Effects of a cannabinoid receptor agonist on colonic motor and sensory functions in humans: a randomized, placebo-controlled study. Am J Physiol Gastrointest Liver Physiol 293:G137–G145

    CAS  PubMed  CrossRef  Google Scholar 

  • Esposito G, Capoccia E, Turco F et al (2013) Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-α activation. Gut 63:1300–1312

    PubMed  CrossRef  CAS  Google Scholar 

  • Feng CC, Yan XJ, Chen X et al (2014) Vagal anandamide signaling via cannabinoid receptor 1 contributes to luminal 5-HT modulation of visceral nociception in rats. Pain 155:1591–1604

    CAS  PubMed  CrossRef  Google Scholar 

  • Fernandez JR, Allison DB (2004) Rimonabant Sanofi-Synthélabo. Curr Opin Investig Drugs 5:430–435

    CAS  PubMed  Google Scholar 

  • Fichna J, Schicho R, Andrews CN et al (2009) Salvinorin A inhibits colonic transit and neurogenic ion transport in mice by activating kappa-opioid and cannabinoid receptors. Neurogastroenterol Motil 21:1326 e128

    CAS  PubMed  CrossRef  Google Scholar 

  • Fichna J, Wood JT, Papanastasiou M et al (2013) Endocannabinoid and cannabinoid-like acid amide levels correlate with pain-related symptoms in patients with IBS-D and IBS-C: a pilot study. PLoS One 8:e85073

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  • Galligan JJ (2009) Cannabinoid signalling in the enteric nervous system. Neurogastroenterol Motil 21:899–902

    CAS  PubMed  CrossRef  Google Scholar 

  • Gaoni Y, Mechoulam R (1964) Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc 86:1646–1647

    CAS  CrossRef  Google Scholar 

  • Greenhough A, Patsos HA, Williams AC et al (2007) The cannabinoid Δ9-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells. Int J Cancer 121:2172–2180

    CAS  PubMed  CrossRef  Google Scholar 

  • Guagnini F, Cogliati P, Mukenge S et al (2006a) Tolerance to cannabinoid response on the myenteric plexus of guinea-pig ileum and human small intestinal strips. Br J Pharmacol 148:1165–1173

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Guagnini F, Valenti M, Mukenge S et al (2006b) Neural contractions in colonic strips from patients with diverticular disease: role of endocannabinoids and substance P. Gut 55:946–953

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Gustafsson SB, Palmqvist R, Henriksson ML et al (2011) High tumour cannabinoid CB 1 receptor immunoreactivity negatively impacts disease-specific survival in stage II microsatellite stable colorectal cancer. PLoS One 6:e23003

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Herkenham M (1991) Characterization and localization of cannabinoid receptors in brain: an in vitro technique using slide-mounted tissue sections. NIDA Res Monogr 112:129–145

    CAS  PubMed  Google Scholar 

  • Hong S, Zheng G, Wiley JW (2015) Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral nervous system. Gastroenterology 148:148–157 e7

    CAS  PubMed  CrossRef  Google Scholar 

  • Izzo AA, Sharkey KA (2010) Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther 126:21–38

    CAS  PubMed  CrossRef  Google Scholar 

  • Izzo AA, Mascolo N, Borrelli F, Capasso F (1998) Excitatory transmission to the circular muscle of the guinea-pig ileum: evidence for the involvement of cannabinoid CB1 receptors. Br J Pharmacol 124:1363–1368

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Izzo AA, Mascolo N, Pinto L et al (1999) The role of cannabinoid receptors in intestinal motility, defaecation and diarrhoea in rats. Eur J Pharmacol 384:37–42

    CAS  PubMed  CrossRef  Google Scholar 

  • Izzo AA, Pinto L, Borrelli F et al (2000) Central and peripheral cannabinoid modulation of gastrointestinal transit in physiological states or during the diarrhoea induced by croton oil. Br J Pharmacol 129:1627–1632

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Izzo AA, Fezza F, Capasso R et al (2001) Cannabinoid CB1-receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation. Br J Pharmacol 134:563–570

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Izzo AA, Capasso F, Costagliola A, Bisogno T,Marsicano G, Ligresti A, Matias I, Capasso R, Pinto L, Borrelli F, Cecio A, Lutz B, Mascolo N, Di Marzo V (2003) An endogenous cannabinoid tone attenuates cholera toxin-induced fluid accumulation in mice. Gastroenterology 125(3):765–74

    Google Scholar 

  • Izzo AA, Aviello G, Petrosino S et al (2008) Increased endocannabinoid levels reduce the development of precancerous lesions in the mouse colon. J Mol Med 86:89–98. doi:10.1007/s00109-007-0248-4

    CAS  PubMed  CrossRef  Google Scholar 

  • Izzo AA, Capasso R, Aviello G et al (2012) Inhibitory effect of cannabichromene, a major non-psychotropic cannabinoid extracted from Cannabis sativa, on inflammation-induced hypermotility in mice. Br J Pharmacol 166:1444–1460

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Jiang Y, Nie Y, Li Y, Zhang L (2014) Association of cannabinoid type 1 receptor and fatty acid amide hydrolase genetic polymorphisms in Chinese patients with irritable bowel syndrome. J Gastroenterol Hepatol 29:1186–1191

    CAS  PubMed  CrossRef  Google Scholar 

  • Jung CK, Kang WK, Park JM et al (2013) Expression of the cannabinoid type I receptor and prognosis following surgery in colorectal cancer. Oncol Lett 5:870–876

    CAS  PubMed  Google Scholar 

  • Kassinen A, Krogius-Kurikka L, Mäkivuokko H et al (2007) The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology 133:24–33

    CAS  PubMed  CrossRef  Google Scholar 

  • Kimball ES, Schneider CR, Wallace NH et al (2006) Agonists of cannabinoid receptor 1 and 2 inhibit experimental colitis induced by oil of mustard and by dextran sulfate sodium. Am J Physiol Gastrointest Liver Physiol 291:G364–G371

    CAS  PubMed  CrossRef  Google Scholar 

  • Kinsey SG, Nomura DK, O’Neal ST et al (2011) Inhibition of monoacylglycerol lipase attenuates nonsteroidal anti-inflammatory drug-induced gastric hemorrhages in mice. J Pharmacol Exp Ther 338:795–802

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Klooker TK, Leliefeld KE, Van Den Wijngaard RM et al (2011) The cannabinoid receptor agonist delta-9-tetrahydrocannabinol does not affect visceral sensitivity to rectal distension in healthy volunteers and IBS patients. Neurogastroenterol Motil 23:30–35 e2

    CAS  PubMed  CrossRef  Google Scholar 

  • Lal S, Prasad N, Ryan M et al (2011) Cannabis use amongst patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 23:891–896

    PubMed  CrossRef  Google Scholar 

  • Lehmann A, Blackshaw LA, Brändén L et al (2002) Cannabinoid receptor agonism inhibits transient lower esophageal sphincter relaxations and reflux in dogs. Gastroenterology 123:1129–1134

    CAS  PubMed  CrossRef  Google Scholar 

  • Li K, Fichna J, Schicho R et al (2013) A role for O-1602 and G protein-coupled receptor GPR55 in the control of colonic motility in mice. Neuropharmacology 71:255–263

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Longstreth GF, Thompson WG, Chey WD et al (2006) Functional bowel disorders. Gastroenterology 130:1480–1491

    PubMed  CrossRef  Google Scholar 

  • Lovell RM, Ford AC (2012) Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol 10:712–721 e4

    PubMed  CrossRef  Google Scholar 

  • Ly HG, Ceccarini J, Weltens N et al (2015) Increased cerebral cannabinoid-1 receptor availability is a stable feature of functional dyspepsia: a [F]MK-9470 PET study. Psychother Psychosom 84:149–158

    PubMed  CrossRef  Google Scholar 

  • MacNaughton WK, Van Sickle MD, Keenan CM et al (2004) Distribution and function of the cannabinoid-1 receptor in the modulation of ion transport in the guinea pig ileum: relationship to capsaicin-sensitive nerves. Am J Physiol Gastrointest Liver Physiol 286:G863–G871

    CAS  PubMed  CrossRef  Google Scholar 

  • Mahadeva S, Ford AC (2016) Clinical and epidemiological differences in functional dyspepsia between the East and the West. Neurogastroenterol Motil 28:167–174

    CAS  PubMed  CrossRef  Google Scholar 

  • Malik Z, Bayman L, Valestin J et al (2016) Dronabinol increases pain threshold in patients with functional chest pain: a pilot double-blind placebo-controlled trial. Dis Esophagus. doi:10.1111/dote.12455

    Google Scholar 

  • Manara L, Croci T, Guagnini F et al (2002) Functional assessment of neuronal cannabinoid receptors in the muscular layers of human ileum and colon. Dig Liver Dis 34:262–269

    CAS  PubMed  CrossRef  Google Scholar 

  • Marquez L, Suarez J, Iglesias M et al (2009) Ulcerative colitis induces changes on the expression of the endocannabinoid system in the human colonic tissue. PLoS One 4:e6893

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  • Martínez-Martínez E, Gómez I, Martín P et al (2015) Cannabinoids receptor type 2, CB2, expression correlates with human colon cancer progression and predicts patient survival. Oncoscience 2:131–141

    PubMed  PubMed Central  CrossRef  Google Scholar 

  • Massa F, Marsicano G, Hermana H et al (2004) The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest 113:1202–1209

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Mathison R, Ho W, Pittman QJ et al (2004) Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats. Br J Pharmacol 142:1247–1254

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Mechoulam R, Ben-Shabat S, Hanus L et al (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90

    CAS  PubMed  CrossRef  Google Scholar 

  • Mulè F, Amato A, Baldassano S, Serio R (2007) Involvement of CB1 and CB2 receptors in the modulation of cholinergic neurotransmission in mouse gastric preparations. Pharmacol Res 56:185–192

    PubMed  CrossRef  CAS  Google Scholar 

  • Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65

    CAS  PubMed  CrossRef  Google Scholar 

  • Naftali T, Lev LB, Yablekovitz D et al (2011) Treatment of Crohn’s disease with cannabis: an observational study. Isr Med Assoc J 13:455–458

    PubMed  Google Scholar 

  • Naftali T, Bar-Lev Schleider L, Dotan I et al (2013) Cannabis induces a clinical response in patients with Crohn’s disease: a prospective placebo-controlled study. Clin Gastroenterol Hepatol 11:1276–1280 e1

    CAS  PubMed  CrossRef  Google Scholar 

  • Naidu PS, Booker L, Cravatt BF, Lichtman AH (2009) Synergy between enzyme inhibitors of fatty acid amide hydrolase and cyclooxygenase in visceral nociception. J Pharmacol Exp Ther 329:48–56

    CAS  PubMed  CrossRef  Google Scholar 

  • Ohman L, Simrén M (2010) Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions. Nat Rev Gastroenterol Hepatol 7:163–173

    PubMed  CrossRef  Google Scholar 

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

    CAS  PubMed  CrossRef  Google Scholar 

  • Osei-Hyiaman D, DePetrillo M, Pacher P et al (2005) Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 115:1298–1305

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Park JM, Choi MG, Cho YK et al (2011) Cannabinoid receptor 1 gene polymorphism and irritable bowel syndrome in the Korean population: a hypothesis-generating study. J Clin Gastroenterol 45:45–49

    CAS  PubMed  CrossRef  Google Scholar 

  • Parker LA, Niphakis MJ, Downey R et al (2015) Effect of selective inhibition of monoacylglycerol lipase (MAGL) on acute nausea, anticipatory nausea, and vomiting in rats and Suncus murinus. Psychopharmacology (Berl) 232:583–593

    CAS  CrossRef  Google Scholar 

  • Pellerito O, Notaro A, Sabella S et al (2014) WIN induces apoptotic cell death in human colon cancer cells through a block of autophagic flux dependent on PPARgamma down-regulation. Apoptosis 19:1029–1042

    CAS  PubMed  Google Scholar 

  • Pertwee RG (2001) Cannabinoids and the gastrointestinal tract. Gut 48:859–867

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Pertwee RG, Fernando SR, Nash JE et al (1996) Further evidence for the presence of cannabinoid CB1 receptors in guinea-pig small intestine. Br J Pharmacol 118:2199–2205

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Pinto L, Izzo AA, Mascolo N et al (2002) Endocannabinoids as physiological regulators of colonic propulsion in mice. Gastroenterology 123:227–234

    CAS  PubMed  CrossRef  Google Scholar 

  • Poonyachoti S, Kulkarni-Narla A, Brown DR (2002) Chemical coding of neurons expressing delta- and kappa-opioid receptor and type I vanilloid receptor immunoreactivities in the porcine ileum. Cell Tissue Res 307:23–33

    CAS  PubMed  CrossRef  Google Scholar 

  • Ravikoff Allegretti J, Courtwright A, Lucci M et al (2013) Marijuana use patterns among patients with inflammatory bowel disease. Inflamm Bowel Dis 19:2809–2814

    PubMed  CrossRef  Google Scholar 

  • Ringel-Kulka T, Goldsmith JR, Carroll IM et al (2014) Lactobacillus acidophilus NCFM affects colonic mucosal opioid receptor expression in patients with functional abdominal pain – a randomised clinical study. Aliment Pharmacol Ther 40:200–207

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Rock EM, Limebeer CL, Parker LA (2014) Anticipatory nausea in animal models: a review of potential novel therapeutic treatments. Exp Brain Res 232:2511–2534

    CAS  PubMed  CrossRef  Google Scholar 

  • Roth SH (1978) Stereospecific presynaptic inhibitory effect of delta9-tetrahydrocannabinol on cholinergic transmission in the myenteric plexus of the guinea pig. Can J Physiol Pharmacol 56:968–975

    CAS  PubMed  CrossRef  Google Scholar 

  • Rousseaux C, Thuru X, Gelot A et al (2007) Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med 13:35–37

    CAS  PubMed  CrossRef  Google Scholar 

  • Rozenfeld R, Bushlin I, Gomes I et al (2012) Receptor heteromerization expands the repertoire of cannabinoid signaling in rodent neurons. PLoS One 7:e29239

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Sakin YS, Dogrul A, Ilkaya F et al (2015) The effect of FAAH, MAGL, and Dual FAAH/MAGL inhibition on inflammatory and colorectal distension-induced visceral pain models in rodents. Neurogastroenterol Motil 27:936–944

    CAS  PubMed  CrossRef  Google Scholar 

  • Sanson M, Bueno L, Fioramonti J (2006) Involvement of cannabinoid receptors in inflammatory hypersensitivity to colonic distension in rats. Neurogastroenterol Motil 18:949–956

    CAS  PubMed  CrossRef  Google Scholar 

  • Santoro A, Pisanti S, Grimaldi C et al (2009) Rimonabant inhibits human colon cancer cell growth and reduces the formation of precancerous lesions in the mouse colon. Int J Cancer 125:996–1003

    CAS  PubMed  CrossRef  Google Scholar 

  • Schicho R, Storr M (2011) Alternative targets within the endocannabinoid system for future treatment of gastrointestinal diseases. Can J Gastroenterol 25:377–383

    PubMed  PubMed Central  CrossRef  Google Scholar 

  • Sharkey KA, Wiley JW (2016) Getting into the weed: the role of the endocannabinoid system in the brain-gut axis. Gastroenterology. doi:10.1053/j.gastro.2016.04.015

    Google Scholar 

  • Sharkey KA, Cristino L, Oland LD et al (2007) Arvanil, anandamide and N-arachidonoyl-dopamine (NADA) inhibit emesis through cannabinoid CB1 and vanilloid TRPV1 receptors in the ferret. Eur J Neurosci 25:2773–2782

    CAS  PubMed  CrossRef  Google Scholar 

  • Silvestri C, Ligresti A, Di Marzo V (2011) Peripheral effects of the endocannabinoid system in energy homeostasis: adipose tissue, liver and skeletal muscle. Rev Endocr Metab Disord 12:153–162

    CAS  PubMed  CrossRef  Google Scholar 

  • Singh UP, Singh NP, Singh B et al (2012) Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10(-/-) mice by attenuating the activation of T cells and promoting their apoptosis. Toxicol Appl Pharmacol 258:256–267

    CAS  PubMed  CrossRef  Google Scholar 

  • Smid SD, Bjorklund CK, Svensson KM et al (2007) The endocannabinoids anandamide and 2-arachidonoylglycerol inhibit cholinergic contractility in the human colon. Eur J Pharmacol 575:168–176

    CAS  PubMed  CrossRef  Google Scholar 

  • Sofia RD, Diamantis W, Edelson J (1978) Effect of delta9-tetrahydrocannabinol on the gastrointestinal tract of the rat. Pharmacology 17:79–82

    CAS  PubMed  CrossRef  Google Scholar 

  • Sticht MA, Long JZ, Rock EM et al (2012) Inhibition of monoacylglycerol lipase attenuates vomiting in Suncus murinus and 2-arachidonoyl glycerol attenuates nausea in rats. Br J Pharmacol 165:2425–2435

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Sticht MA, Limebeer CL, Rafla BR et al (2015) Intra-visceral insular cortex 2-arachidonoylglycerol, but not N-arachidonoylethanolamide, suppresses acute nausea-induced conditioned gaping in rats. Neuroscience 286:338–344

    CAS  PubMed  CrossRef  Google Scholar 

  • Storr M, Sibaev A, Marsicano G et al (2004) Cannabinoid receptor type 1 modulates excitatory and inhibitory neurotransmission in mouse colon. Am J Physiol Gastrointest Liver Physiol 286:G110–G117

    CAS  PubMed  CrossRef  Google Scholar 

  • Storr MA, Keenan CM, Emmerdinger D et al (2008) Targeting endocannabinoid degradation protects against experimental colitis in mice: involvement of CB1 and CB2 receptors. J Mol Med 86:925–936

    CAS  PubMed  CrossRef  Google Scholar 

  • Storr MA, Keenan CM, Zhang H et al (2009) Activation of the cannabinoid 2 receptor (CB2) protects against experimental colitis. Inflamm Bowel Dis 15:1678–1685

    PubMed  CrossRef  Google Scholar 

  • Storr M, Devlin S, Kaplan GG et al (2014) Cannabis use provides symptom relief in patients with inflammatory bowel disease but is associated with worse disease prognosis in patients with Crohn’s disease. Inflamm Bowel Dis 20:472–480

    PubMed  CrossRef  Google Scholar 

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

    CAS  PubMed  CrossRef  Google Scholar 

  • Tack J, Piessevaux H, Coulie B et al (1998) Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology 115:1346–1352

    CAS  PubMed  CrossRef  Google Scholar 

  • Taschler U, Eichmann TO, Radner FPW et al (2015) Monoglyceride lipase-deficiency causes desensitization of intestinal cannabinoid receptor type 1 and increased colonic μ-opioid receptor sensitivity. Br J Pharmacol 172:4419–4429

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Trautmann SM, Sharkey KA (2015) The endocannabinoid system and its role in regulating the intrinsic neural circuitry of the gastrointestinal tract. Int Rev Neurobiol 125:85–126

    PubMed  CrossRef  Google Scholar 

  • Tyler K, Hillard CJ, Greenwood-Van Meerveld B (2000) Inhibition of small intestinal secretion by cannabinoids is CB1 receptor-mediated in rats. Eur J Pharmacol 409:207–211

    CAS  PubMed  CrossRef  Google Scholar 

  • Van Sickle MD, Duncan M, Kingsley PJ et al (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310:329–332

    CAS  PubMed  CrossRef  Google Scholar 

  • Velasco G, Sánchez C, Guzmán M (2012) Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer 12:436–444

    CAS  PubMed  CrossRef  Google Scholar 

  • Vianna CR, Donato J Jr, Rossi J et al (2012) Cannabinoid receptor 1 in the vagus nerve is dispensable for body weight homeostasis but required for normal gastrointestinal motility. J Neurosci 32:10331–10337

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Wang D, Wang H, Ning W et al (2008) Loss of cannabinoid receptor 1 accelerates intestinal tumor growth. Cancer Res 68:6468–6476

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Ward SM, Bayguinov J, Won KJ et al (2003) Distribution of the vanilloid receptor (VR1) in the gastrointestinal tract. J Comp Neurol 465:121–135

    PubMed  CrossRef  Google Scholar 

  • Warzecha Z, Dembinski A, Ceranowicz P et al (2011) Role of sensory nerves in gastroprotective effect of anandamide in rats. J Physiol Pharmacol 62:207–217

    CAS  PubMed  Google Scholar 

  • Wong BS, Camilleri M, Busciglio I et al (2011) Pharmacogenetic trial of a cannabinoid agonist shows reduced fasting colonic motility in patients with nonconstipated irritable bowel syndrome. Gastroenterology 141:1638–1647.e1–7

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Wong BS, Camilleri M, Eckert D et al (2012) Randomized pharmacodynamic and pharmacogenetic trial of dronabinol effects on colon transit in irritable bowel syndrome-diarrhea. Neurogastroenterol Motil 24:358-e169

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  • Wright K, Rooney N, Feeney M, Tate J, Robertson D, Welham M, Ward S (2005) Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing. Gastroenterology 129(2):437–53

    Google Scholar 

  • Ye L, Zhang B, Seviour EG et al (2011) Monoacylglycerol lipase (MAGL) knockdown inhibits tumor cells growth in colorectal cancer. Cancer Lett 307:6–17

    CAS  PubMed  CrossRef  Google Scholar 

  • Zheng G, Hong S, Hayes JM et al (2015) Chronic stress and peripheral pain: evidence for distinct, region-specific changes in visceral and somatosensory pain regulatory pathways. Exp Neurol 273:301–311

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

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Taschler, U., Hasenoehrl, C., Storr, M., Schicho, R. (2016). Cannabinoid Receptors in Regulating the GI Tract: Experimental Evidence and Therapeutic Relevance. In: Greenwood-Van Meerveld, B. (eds) Gastrointestinal Pharmacology . Handbook of Experimental Pharmacology, vol 239. Springer, Cham. https://doi.org/10.1007/164_2016_105

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