title: Novel orally available salvinorin A analog PR-38 protects against experimental colitis and reduces abdominal pain in mice by interaction with opioid and cannabinoid receptors.
abstract: BACKGROUND
  Salvinorin A (SA) is a potent anti-inflammatory diterpene isolated from the Mexican plant S. divinorum. Recently we showed that the novel SA analog, PR-38 has an inhibitory effect on mouse gastrointestinal (GI) motility mediated by opioid and cannabinoid (CB) receptors. The aim of the study was to characterize possible anti-inflammatory and antinociceptive action of PR-38 in the mouse GI tract.
  
  
  METHODS
  Macro- and microscopic colonic damage scores and myeloperoxidase activity were determined after intraperitoneal (i.p.), intracolonic (i.c.), and per os (p.o.) administration of PR-38 in the trinitrobenzene sulfonic acid (TNBS) and dextran sodium sulfate (DSS) models of colitis in mice. Additionally, MOP, KOP and CB1 protein expression was determined using Western blot analysis of mouse colon samples. The antinociceptive effect of PR-38 was examined based on the number of behavioral responses to i.c. instillation of mustard oil (MO).
  
  
  RESULTS
  The i.p. (10 mg/kg, twice daily), i.c. (10 mg/kg, twice daily) and p.o. (20 mg/kg, once daily) administration of PR-38 significantly attenuated TNBS- and DSS-induced colitis in mice. The effect of PR-38 was partially blocked by the KOP antagonist nor-binaltorphimine and CB1 antagonist AM 251. Western blot analysis showed a significant increase of MOP, KOP and CB1 receptor expression during colonic inflammation, which was reversed to the control levels by the administration of PR-38. PR-38 significantly decreased the number of pain responses after i.c. instillation of MO in the TNBS-treated mice.
  
  
  CONCLUSIONS
  Our results suggest that PR-38 has the potential to become a valuable anti-inflammatory and analgesic therapeutic for the treatment of GI inflammation.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Sałaga
authors.affiliation: Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS, USA.
authors.forename: Prabhakar Reddy
authors.initials: PR
authors.lastname: Polepally
authors.affiliation: Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.
authors.forename: Piotr K
authors.initials: PK
authors.lastname: Zakrzewski
authors.affiliation: Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Cygankiewicz
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Sobczak
authors.affiliation: Department of Pathology, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
authors.forename: Radzisław
authors.initials: R
authors.lastname: Kordek
authors.affiliation: Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS, USA.
authors.forename: Jordan K
authors.initials: JK
authors.lastname: Zjawiony
authors.affiliation: Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.
authors.forename: Wanda M
authors.initials: WM
authors.lastname: Krajewska
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland. Electronic address: jakub.fichna@umed.lodz.pl.
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
mesh_terms: D015746:Abdominal Pain / Q000517:prevention & control*; D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000517:prevention & control*; D045785:Diterpenes, Clerodane / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D043882:Receptors, Cannabinoid / Q000187:drug effects*; D011957:Receptors, Opioid / Q000187:drug effects*; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
chemical_list: C000590927:2-O-cinnamoylsalvinorin B; D000700:Analgesics; D045785:Diterpenes, Clerodane; D043882:Receptors, Cannabinoid; D011957:Receptors, Opioid; D014302:Trinitrobenzenesulfonic Acid
keywords: Experimental colitis; Inflammatory bowel diseases; Intestinal inflammation; PR-38