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Inflamm Bowel Dis. 2011 Aug;17(8):1651-64. doi: 10.1002/ibd.21538. Epub 2010 Nov 15.

The atypical cannabinoid O-1602 protects against experimental colitis and inhibits neutrophil recruitment.

Author information

1
Division of Gastroenterology, Department of Medicine, Snyder Institute of Infection, Immunity and Inflammation (III), Alberta, Canada.

Abstract

BACKGROUND:

Cannabinoids are known to reduce intestinal inflammation. Atypical cannabinoids produce pharmacological effects via unidentified targets. We were interested in whether the atypical cannabinoid O-1602, reportedly an agonist of the putative cannabinoid receptor GPR55, reduces disease severity of dextran sulfate sodium (DSS) and trinitrobenzene sulfonic acid (TNBS)-induced colitis in C57BL/6N and CD1 mice.

METHODS:

DSS (2.5% and 4%) was supplied in drinking water for 1 week while TNBS (4 mg) was applied as a single intrarectal bolus.

RESULTS:

Both treatments caused severe colitis. Injection of O-1602 (5 mg/kg intraperitoneally) significantly reduced macroscopic and histological colitis scores, and myeloperoxidase activity. The protective effect was still present in cannabinoid receptor 1 (CB₁) and 2 (CB₂) double knockout mice and mice lacking the GPR55 gene. To investigate a potential mechanism underlying the protection by O-1602 we performed neutrophil chemotactic assays. O-1602 concentration-dependently inhibited migration of murine neutrophils to keratinocyte-derived chemokine (KC), N-formyl-methionyl-leucyl-phenylalanine (fMLP), and the N-formyl-peptide receptor ligand WKYMVm. The inhibitory effect of O-1602 was preserved in neutrophils from CB₁/CB₂ double knockout and GPR55 knockout mice. No differences were seen in locomotor activity between O-1602-treated and control mice, indicating lack of central sedation by this compound.

CONCLUSIONS:

Our data demonstrate that O-1602 is protective against experimentally induced colitis and inhibits neutrophil recruitment independently of CB₁, CB₂, and GPR55 receptors. Thus, atypical cannabinoids represent a novel class of therapeutics that may be useful for the treatment of inflammatory bowel diseases.

PMID:
21744421
PMCID:
PMC3116968
DOI:
10.1002/ibd.21538
[Indexed for MEDLINE]
Free PMC Article
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