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

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.

Our data demonstrate that O-1602 is protective against experimentally induced colitis and inhibits neutrophil recruitment independently of CB&sub1;, CB&sub2;, and GPR55 receptors. Thus, atypical cannabinoids represent a novel class of therapeutics that may be useful for the treatment of inflammatory bowel diseases.

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

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 (CB&sub1;) and 2 (CB&sub2;) 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 CB&sub1;/CB&sub2; 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 CB&sub1;, CB&sub2;, and GPR55 receptors. Thus, atypical cannabinoids represent a novel class of therapeutics that may be useful for the treatment of inflammatory bowel diseases.