title: Salvinorin A has antiinflammatory and antinociceptive effects in experimental models of colitis in mice mediated by KOR and CB1 receptors.
abstract: BACKGROUND
  Salvinorin A (SA) has a potent inhibitory action on mouse gastrointestinal (GI) motility and ion transport, mediated primarily by kappa-opioid receptors (KOR). The aim of the present study was to characterize possible antiinflammatory and antinociceptive effects of SA in the GI tract of mice.
  
  
  METHODS
  Colonic damage scores and myeloperoxidase activity were determined after intraperitoneal (i.p.), intracolonic (i.c.), and oral (p.o.) administration of SA using the trinitrobenzene sulfonic acid (TNBS) and dextran sodium sulfate (DSS) models of colitis in mice. Additionally, KOR, cannabinoid (CB)1, and CB2 western blot analysis of colon samples was performed. The antinociceptive effect of SA was examined based on the number of behavioral responses to i.c. instillation of mustard oil (MO).
  
  
  RESULTS
  The i.p. (3 mg/kg, twice daily) and p.o. (10 mg/kg, twice daily) administration of SA significantly attenuated TNBS and DSS colitis in mice. The effect of SA was blocked by KOR antagonist nor-binaltorphimine (10 mg/kg, i.p.). Western blot analysis showed no influence of SA on KOR, CB1, or CB2 levels. SA (3 mg/kg, i.p. and 10 mg/kg, i.c.) significantly decreased the number of pain responses after i.c. instillation of MO in the vehicle- and TNBS-treated mice. The antinociceptive action of SA was blocked by KOR and CB1 antagonists. The analgesic effect of i.c. SA was more potent in TNBS-treated mice compared to controls.
  
  
  CONCLUSIONS
  Our results suggest that the drugs based on the structure of SA have the potential to become valuable antiinflammatory or analgesic therapeutics for the treatment of GI diseases.
authors.affiliation: Snyder Institute of Infection, Immunity and Inflammation (III), University of Calgary, AB, Canada.
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
authors.forename: Michael
authors.initials: M
authors.lastname: Dicay
authors.forename: Kevin
authors.initials: K
authors.lastname: Lewellyn
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
authors.forename: Jordan K
authors.initials: JK
authors.lastname: Zjawiony
authors.forename: Wallace K
authors.initials: WK
authors.lastname: MacNaughton
authors.forename: Martin A
authors.initials: MA
authors.lastname: Storr
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D045785:Diterpenes, Clerodane / Q000627:therapeutic use*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D008297:Male; D051379:Mice; D009271:Naltrexone / Q000031:analogs & derivatives; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D009195:Peroxidase; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D027544:Salvia / Q000737:chemistry; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D045785:Diterpenes, Clerodane; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D009271:Naltrexone; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D009195:Peroxidase; C090499:salvinorin A