beta-funaltrexamine and Irritable-Bowel-Syndrome

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a functional disorder of the gastrointestinal (GI) tract. The major IBS-D symptoms include diarrhea, abdominal pain and discomfort. High density of opioid receptors (ORs) in the GI tract and their participation in the maintenance of GI homeostasis make ORs ligands an attractive option for developing new anti-IBS-D treatments. The aim of this study was to characterize the effect of methyl-orvinol on the GI motility and secretion and in mouse models mimicking symptoms of IBS-D.. In vitro, the effects of methyl-orvinol on electrical field stimulated smooth muscle contractility and epithelial ion transport were characterized in the mouse colon. In vivo, the following tests were used to determine methyl-orvinol effect on mouse GI motility: colonic bead expulsion, whole GI transit and fecal pellet output. An antinociceptive action of methyl-orvinol was assessed in the mouse model of visceral pain induced by mustard oil.. Methyl-orvinol (10. Methyl-orvinol could become a promising drug candidate in chronic therapy of functional GI diseases such as IBS-D.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Abdominal Pain; Analgesics; Analgesics, Opioid; Animals; Colon; Diarrhea; Disease Models, Animal; Gastrointestinal Motility; Gastrointestinal Transit; Irritable Bowel Syndrome; Male; Mice; Mice, Inbred BALB C; Muscle Contraction; Muscle, Smooth; Naloxone; Naltrexone; Receptors, Opioid; Thebaine

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.

Topics: Abdominal Pain; Administration, Oral; Animals; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Diarrhea; Disease Models, Animal; Diterpenes, Clerodane; Dose-Response Relationship, Drug; Exploratory Behavior; Gastrointestinal Motility; Injections, Intraperitoneal; Irritable Bowel Syndrome; Male; Mice; Motor Activity; Naltrexone; Receptors, Opioid, kappa; Receptors, Opioid, mu