title: Differential effects of salvinorin A on endotoxin-induced hypermotility and neurogenic ion transport in mouse ileum.
abstract: BACKGROUND
  Salvinorin A (SA) is the principal active ingredient of Salvia divinorum, with an established inhibitory action on gastrointestinal (GI) transit and colonic ion transport in mice. Under normal conditions, the effects of SA are mediated by kappa opioid (KOR) and cannabinoid (CB1 and CB2) receptors. However, the role of SA in pathophysiological conditions remains unresolved. The aim of this study was to characterize the in vitro and in vivo effects of SA on mouse ileum after endotoxin challenge.
  
  
  METHODS
  Changes in GI motility were studied in vitro, using smooth muscle preparations from the mouse ileum. In vivo, the fecal pellet output and small intestinal fluid content were measured. Neurogenic ion transport and intestinal permeability were examined using Ussing chambers. In addition, Western blot analysis of mucosa was performed and plasma nitrite/nitrate levels were determined.
  
  
  RESULTS
  Salvinorin A inhibited endotoxin-induced ileal hypercontractility via KOR, CB1, and CB2 receptors. Neurogenic ion transport, which was significantly reduced after endotoxin challenge, was normalized by SA through a nitric oxide synthase (NOS)-dependent mechanism. Western blot analysis and plasma nitrite/nitrate level quantitation confirmed the involvement of NOS in the regulatory action of SA.
  
  
  CONCLUSIONS
  This is the first report showing differential effects of SA on motor and secretory activity in mouse GI during endotoxemia. The outcomes of our study imply possible novel applications of SA and its analogs in the treatment of GI disorders.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Snyder Institute of Infection, Immunity and Inflammation (III), University of Calgary, Calgary, AB, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Fichna
authors.forename: M
authors.initials: M
authors.lastname: Dicay
authors.forename: S A
authors.initials: SA
authors.lastname: Hirota
authors.forename: D
authors.initials: D
authors.lastname: Traboulsi
authors.forename: J A
authors.initials: JA
authors.lastname: Macdonald
authors.forename: A
authors.initials: A
authors.lastname: Janecka
authors.forename: P L
authors.initials: PL
authors.lastname: Beck
authors.forename: J K
authors.initials: JK
authors.lastname: Zjawiony
authors.forename: W K
authors.initials: WK
authors.lastname: Macnaughton
authors.forename: M A
authors.initials: MA
authors.lastname: Storr
mesh_terms: D000818:Animals; D003672:Defecation / Q000187:drug effects; D045785:Diterpenes, Clerodane / Q000494:pharmacology*; D004731:Endotoxins / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007082:Ileum / Q000187:drug effects* / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects*; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism
chemical_list: D045785:Diterpenes, Clerodane; D004731:Endotoxins; D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C090499:salvinorin A