title: Novel orally available salvinorin A analog PR-38 inhibits gastrointestinal motility and reduces abdominal pain in mouse models mimicking irritable bowel syndrome.
abstract: The opioid and cannabinoid systems play a crucial role in multiple physiological processes in the central nervous system and in the periphery. Selective opioid as well as cannabinoid (CB) receptor agonists exert a potent inhibitory action on gastrointestinal (GI) motility and pain. In this study, we examined (in vitro and in vivo) whether PR-38 (2-O-cinnamoylsalvinorin B), a novel analog of salvinorin A, can interact with both systems and demonstrate therapeutic effects. We used mouse models of hypermotility, diarrhea, and abdominal pain. We also assessed the influence of PR-38 on the central nervous system by measurement of motoric parameters and exploratory behaviors in mice. Subsequently, we investigated the pharmacokinetics of PR-38 in mouse blood samples after intraperitoneal and oral administration. PR-38 significantly inhibited mouse colonic motility in vitro and in vivo. Administration of PR-38 significantly prolonged the whole GI transit time, and this effect was mediated by µ- and κ-opioid receptors and the CB1 receptor. PR-38 reversed hypermotility and reduced pain in mouse models mimicking functional GI disorders. These data expand our understanding of the interactions between opioid and cannabinoid systems and their functions in the GI tract. We also provide a novel framework for the development of future potential treatments of functional GI disorders.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland (M.Sa., M.So., J.F.); Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.); Research and Development Laboratory, Lipopharm.pl, Zblewo, Poland (D.G.); Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Poland (W.K.); Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Munich, Germany (A.S., M.St.); and Platform of Behavioural Analysis, Institute for Research and Innovation in Biomedicine, Faculty of Medicine and Pharmacy, University of Rouen, Rouen Cedex, France (J.C.D.R.).
authors.forename: M
authors.initials: M
authors.lastname: Sałaga
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland (M.Sa., M.So., J.F.); Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.); Research and Development Laboratory, Lipopharm.pl, Zblewo, Poland (D.G.); Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Poland (W.K.); Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Munich, Germany (A.S., M.St.); and Platform of Behavioural Analysis, Institute for Research and Innovation in Biomedicine, Faculty of Medicine and Pharmacy, University of Rouen, Rouen Cedex, France (J.C.D.R.).
authors.forename: P R
authors.initials: PR
authors.lastname: Polepally
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland (M.Sa., M.So., J.F.); Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.); Research and Development Laboratory, Lipopharm.pl, Zblewo, Poland (D.G.); Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Poland (W.K.); Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Munich, Germany (A.S., M.St.); and Platform of Behavioural Analysis, Institute for Research and Innovation in Biomedicine, Faculty of Medicine and Pharmacy, University of Rouen, Rouen Cedex, France (J.C.D.R.).
authors.forename: M
authors.initials: M
authors.lastname: Sobczak
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland (M.Sa., M.So., J.F.); Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.); Research and Development Laboratory, Lipopharm.pl, Zblewo, Poland (D.G.); Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Poland (W.K.); Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Munich, Germany (A.S., M.St.); and Platform of Behavioural Analysis, Institute for Research and Innovation in Biomedicine, Faculty of Medicine and Pharmacy, University of Rouen, Rouen Cedex, France (J.C.D.R.).
authors.forename: D
authors.initials: D
authors.lastname: Grzywacz
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland (M.Sa., M.So., J.F.); Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.); Research and Development Laboratory, Lipopharm.pl, Zblewo, Poland (D.G.); Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Poland (W.K.); Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Munich, Germany (A.S., M.St.); and Platform of Behavioural Analysis, Institute for Research and Innovation in Biomedicine, Faculty of Medicine and Pharmacy, University of Rouen, Rouen Cedex, France (J.C.D.R.).
authors.forename: W
authors.initials: W
authors.lastname: Kamysz
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland (M.Sa., M.So., J.F.); Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.); Research and Development Laboratory, Lipopharm.pl, Zblewo, Poland (D.G.); Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Poland (W.K.); Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Munich, Germany (A.S., M.St.); and Platform of Behavioural Analysis, Institute for Research and Innovation in Biomedicine, Faculty of Medicine and Pharmacy, University of Rouen, Rouen Cedex, France (J.C.D.R.).
authors.forename: A
authors.initials: A
authors.lastname: Sibaev
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland (M.Sa., M.So., J.F.); Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.); Research and Development Laboratory, Lipopharm.pl, Zblewo, Poland (D.G.); Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Poland (W.K.); Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Munich, Germany (A.S., M.St.); and Platform of Behavioural Analysis, Institute for Research and Innovation in Biomedicine, Faculty of Medicine and Pharmacy, University of Rouen, Rouen Cedex, France (J.C.D.R.).
authors.forename: M
authors.initials: M
authors.lastname: Storr
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland (M.Sa., M.So., J.F.); Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.); Research and Development Laboratory, Lipopharm.pl, Zblewo, Poland (D.G.); Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Poland (W.K.); Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Munich, Germany (A.S., M.St.); and Platform of Behavioural Analysis, Institute for Research and Innovation in Biomedicine, Faculty of Medicine and Pharmacy, University of Rouen, Rouen Cedex, France (J.C.D.R.).
authors.forename: J C
authors.initials: JC
authors.lastname: Do Rego
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland (M.Sa., M.So., J.F.); Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.); Research and Development Laboratory, Lipopharm.pl, Zblewo, Poland (D.G.); Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Poland (W.K.); Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Munich, Germany (A.S., M.St.); and Platform of Behavioural Analysis, Institute for Research and Innovation in Biomedicine, Faculty of Medicine and Pharmacy, University of Rouen, Rouen Cedex, France (J.C.D.R.).
authors.forename: J K
authors.initials: JK
authors.lastname: Zjawiony
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland (M.Sa., M.So., J.F.); Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (P.R.P., J.K.Z.); Research and Development Laboratory, Lipopharm.pl, Zblewo, Poland (D.G.); Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Poland (W.K.); Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Munich, Germany (A.S., M.St.); and Platform of Behavioural Analysis, Institute for Research and Innovation in Biomedicine, Faculty of Medicine and Pharmacy, University of Rouen, Rouen Cedex, France (J.C.D.R.) jakub.fichna@umed.lodz.pl.
authors.forename: J
authors.initials: J
authors.lastname: Fichna
mesh_terms: D015746:Abdominal Pain / Q000150:complications / Q000188:drug therapy*; D000284:Administration, Oral; D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D003967:Diarrhea / Q000150:complications / Q000188:drug therapy; D004195:Disease Models, Animal; D045785:Diterpenes, Clerodane / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000188:drug therapy*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors
chemical_list: C000590927:2-O-cinnamoylsalvinorin B; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D045785:Diterpenes, Clerodane; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009271:Naltrexone; C024524:beta-funaltrexamine; C090499:salvinorin A