title: Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability.
abstract: OBJECTIVE
  Activation of cannabinoid receptors decreases emesis, inflammation, gastric acid secretion and intestinal motility. The ability to modulate intestinal permeability in inflammation may be important in therapy aimed at maintaining epithelial barrier integrity. The aim of the present study was to determine whether cannabinoids modulate the increased permeability associated with inflammation in vitro.
  
  
  METHODS
  Confluent Caco-2 cell monolayers were treated for 24 h with IFNγ and TNFα (10 ng·mL(-1) ). Monolayer permeability was measured using transepithelial electrical resistance and flux measurements. Cannabinoids were applied either apically or basolaterally after inflammation was established. Potential mechanisms of action were investigated using antagonists for CB(1) , CB(2) , TRPV1, PPARγ and PPARα. A role for the endocannabinoid system was established using inhibitors of the synthesis and degradation of endocannabinoids.
  
  
  RESULTS
  Δ(9) -Tetrahydrocannabinol (THC) and cannabidiol accelerated the recovery from cytokine-induced increased permeability; an effect sensitive to CB(1) receptor antagonism. Anandamide and 2-arachidonylglycerol further increased permeability in the presence of cytokines; this effect was also sensitive to CB(1) antagonism. No role for the CB(2) receptor was identified in these studies. Co-application of THC, cannabidiol or a CB(1) antagonist with the cytokines ameliorated their effect on permeability. Inhibiting the breakdown of endocannabinoids worsened, whereas inhibiting the synthesis of endocannabinoids attenuated, the increased permeability associated with inflammation.
  
  
  CONCLUSIONS
  These findings suggest that locally produced endocannabinoids, acting via CB(1) receptors play a role in mediating changes in permeability with inflammation, and that phytocannabinoids have therapeutic potential for reversing the disordered intestinal permeability associated with inflammation.
  
  
  BACKGROUND
  This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.
authors: School of Graduate Entry Medicine & Health, Derby City General Hospital, University of Nottingham, Derby, UK.
authors: A
authors: A
authors: Alhamoruni
authors: K L
authors: KL
authors: Wright
authors: M
authors: M
authors: Larvin
authors: S E
authors: SE
authors: O'Sullivan
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D001549:Benzamides / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D018938:Caco-2 Cells; D002186:Cannabinoids / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors; D010539:Permeability / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001549:Benzamides; D052117:Benzodioxoles; D002186:Cannabinoids; D002219:Carbamates; D004791:Enzyme Inhibitors; D007211:Indoles; D007371:Interferon-gamma; D008994:Monoacylglycerol Lipases; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D014409:Tumor Necrosis Factor-alpha; D000099252:Fatty Acid Amide Hydrolases; C534333:JZL 184; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C103505:AM 251; C094023:iodopravadoline