title: The atypical cannabinoid O-1602 protects against experimental colitis and inhibits neutrophil recruitment.
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.
authors: Division of Gastroenterology, Department of Medicine, Snyder Institute of Infection, Immunity and Inflammation (III), Alberta, Canada.
authors: Rudolf
authors: R
authors: Schicho
authors: Mohammad
authors: M
authors: Bashashati
authors: Misha
authors: M
authors: Bawa
authors: Douglas
authors: D
authors: McHugh
authors: Dieter
authors: D
authors: Saur
authors: Huang-Ming
authors: HM
authors: Hu
authors: Andreas
authors: A
authors: Zimmer
authors: Beat
authors: B
authors: Lutz
authors: Ken
authors: K
authors: Mackie
authors: Heather B
authors: HB
authors: Bradshaw
authors: Donna-Marie
authors: DM
authors: McCafferty
authors: Keith A
authors: KA
authors: Sharkey
authors: Martin
authors: M
authors: Storr
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002185:Cannabidiol / Q000031:analogs & derivatives; D002186:Cannabinoids / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003510:Cyclohexanes / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics; D012118:Resorcinols / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D002186:Cannabinoids; D003510:Cyclohexanes; C524885:GPR55 protein, human; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; D012118:Resorcinols; D002185:Cannabidiol; C568537:O-1602 compound; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D009195:Peroxidase