title: Evidence for the putative cannabinoid receptor (GPR55)-mediated inhibitory effects on intestinal contractility in mice.
abstract: BACKGROUND
  Cannabinoids inhibit intestinal motility via presynaptic cannabinoid receptor type I (CB1) in enteric neurons while cannabinoid receptor type II (CB2) receptors are located mainly in immune cells. The recently de-orphanized G-protein-coupled receptor, GPR55, has been proposed to be the 'third' cannabinoid receptor. Although gene expression of GPR55 is evident in the gut, functional evidence for GPR55 in the gut is unknown. In this study, we tested the hypothesis that GPR55 activation inhibits neurogenic contractions in the gut.
  
  
  METHODS
  We assessed the inhibitory effect of the atypical cannabinoid O-1602, a GPR55 agonist, in mouse colon. Isometric tension recordings in colonic tissue strips were used from either wild-type, GPR55(-/-) or CB1(-/-)/CB2(-/-) knockout mice.
  
  
  RESULTS
  O-1602 inhibited the electrical field- induced contractions in the colon strips from wild-type and CB1(-/-)/CB2(-/-) in a concentration-dependent manner, suggesting a non-CB1/CB2 receptor-mediated prejunctional effect. The concentration-dependent response of O-1602 was significantly inhibited in GPR55(-/-) mice. O-1602 did not relax colonic strips precontracted with high K(+) (80 mmol/l), indicating no involvement of Ca(2+) channel blockade in O-1602-induced relaxation. However, 10 µmol/l O-1602 partially inhibited the exogenous acetylcholine (10 µmol/l)-induced contractions. Moreover, we also assessed the inhibitory effects of JWH015, a CB2/GPR55 agonist on neurogenic contractions of mouse ileum. Surprisingly, the effects of JWH015 were independent of the known cannabinoid receptors.
  
  
  CONCLUSIONS
  Taken together, these findings suggest that activation of GPR55 leads to inhibition of neurogenic contractions in the gut and are predominantly prejunctional.
authors: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298-0613, USA. grross@vcu.edu
authors: Gracious R
authors: GR
authors: Ross
authors: Aron
authors: A
authors: Lichtman
authors: William L
authors: WL
authors: Dewey
authors: Hamid I
authors: HI
authors: Akbarali
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002185:Cannabidiol / Q000031:analogs & derivatives; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D003510:Cyclohexanes / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D043882:Receptors, Cannabinoid / Q000502:physiology*; D012118:Resorcinols / Q000494:pharmacology*
chemical_list: D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D003510:Cyclohexanes; C526692:GPR55 protein, mouse; D043882:Receptors, Cannabinoid; D012118:Resorcinols; D002185:Cannabidiol; C568537:O-1602 compound; D000109:Acetylcholine