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The endogenous cannabinoid system protects against colonic inflammation

Academic Article
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Overview

authors

  • Massa, F.
  • Marsicano, G.
  • Hermann, H.
  • Cannich, A.
  • Monory, K.
  • Cravatt, Benjamin
  • Ferri, G. L.
  • Sibaev, A.
  • Storr, M.
  • Lutz, B.

publication date

  • April 2004

journal

  • Journal of Clinical Investigation  Journal

abstract

  • Excessive inflammatory responses can emerge as a potential danger for organisms' health. Physiological balance between pro- and anti-inflammatory processes constitutes an important feature of responses against harmful events. Here, we show that cannabinoid receptors type 1 (CB1) mediate intrinsic protective signals that counteract proinflammatory responses. Both intrarectal infusion of 2,4-dinitrobenzene sulfonic acid (DNBS) and oral administration of dextrane sulfate sodium induced stronger inflammation in CB1-deficient mice (CB1(-/-)) than in wild-type littermates (CB1(+/+)). Treatment of wild-type mice with the specific CB1 antagonist N-(piperidino-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide (SR141716A) mimicked the phenotype of CB1(-/-) mice, showing an acute requirement of CB1 receptors for protection from inflammation. Consistently, treatment with the cannabinoid receptor agonist R(-)-7-hydroxy-Delta(6)-tetra-hydrocannabinol-dimethylheptyl (HU210) or genetic ablation of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) resulted in protection against DNBS-induced colitis. Electrophysiological recordings from circular smooth muscle cells, performed 8 hours after DNBS treatment, revealed spontaneous oscillatory action potentials in CB1(-/-) but not in CB1(+/+) colons, indicating an early CB1-mediated control of inflammation-induced irritation of smooth muscle cells. DNBS treatment increased the percentage of myenteric neurons expressing CB1 receptors, suggesting an enhancement of cannabinoid signaling during colitis. Our results indicate that the endogenous cannabinoid system represents a promising therapeutic target for the treatment of intestinal disease conditions characterized by excessive inflammatory responses.

subject areas

  • Amidohydrolases
  • Animals
  • Colitis
  • Dinitrofluorobenzene
  • Dronabinol
  • Female
  • Gene Expression Regulation
  • Mice
  • Mice, Inbred C57BL
  • Piperidines
  • Pyrazoles
  • RNA, Messenger
  • Receptor, Cannabinoid, CB1
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Identity

PubMed Central ID

  • PMC385396

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/jci200419465

PubMed ID

  • 15085199
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Additional Document Info

start page

  • 1202

end page

  • 1209

volume

  • 113

issue

  • 8

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