Novel orally available salvinorin A analog PR-38 inhibits gastrointestinal motility and reduces abdominal pain in mouse models mimicking irritable bowel syndrome

J Pharmacol Exp Ther. 2014 Jul;350(1):69-78. doi: 10.1124/jpet.114.214239.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abdominal Pain / complications
  • Abdominal Pain / drug therapy*
  • Administration, Oral
  • Animals
  • Cannabinoid Receptor Agonists / pharmacology*
  • Cannabinoid Receptor Antagonists / pharmacology
  • Diarrhea / complications
  • Diarrhea / drug therapy
  • Disease Models, Animal
  • Diterpenes, Clerodane / administration & dosage
  • Diterpenes, Clerodane / chemistry
  • Diterpenes, Clerodane / pharmacology
  • Diterpenes, Clerodane / therapeutic use*
  • Dose-Response Relationship, Drug
  • Exploratory Behavior / drug effects
  • Gastrointestinal Motility / drug effects*
  • Injections, Intraperitoneal
  • Irritable Bowel Syndrome / complications
  • Irritable Bowel Syndrome / drug therapy*
  • Male
  • Mice
  • Motor Activity / drug effects
  • Naltrexone / analogs & derivatives
  • Naltrexone / pharmacology
  • Receptors, Opioid, kappa / antagonists & inhibitors*
  • Receptors, Opioid, mu / agonists*
  • Receptors, Opioid, mu / antagonists & inhibitors

Substances

  • 2-O-cinnamoylsalvinorin B
  • Cannabinoid Receptor Agonists
  • Cannabinoid Receptor Antagonists
  • Diterpenes, Clerodane
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Naltrexone
  • beta-funaltrexamine
  • salvinorin A