beta-funaltrexamine and Diarrhea

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

We investigated the antinociceptive effect of FR140423, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl] pyrazole, in the tail-pinch test in mice, and evaluated the mechanism of action using various opioid receptor antagonists. P.o. and i.t. injection of FR140423 exerted dose-dependent antinociceptive activities with ED50 values of 21 mg/kg and 3.1 microg/mouse, respectively. However, i.c.v. injection of FR140423 did not show an antinociceptive effect. The antinociceptive effects of FR140423 were completely abolished by naloxone and naltrindole but not by naloxonazine, beta-funaltrexamine and nor-binaltorphimine. FR140423 did not affect any opioid receptor binding in mouse spinal membranes at concentrations up to 100 microM in vitro. Naloxone-induced jumping and diarrhea tests for morphine-like physical dependence of FR140423 gave negative results. These results suggest that FR140423 can induce antinociception by acting on the spinal but not the supraspinal site, and that spinal delta-opioid systems indirectly play a role in the antinociception produced by FR140423 in mice.

Topics: Administration, Oral; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Binding, Competitive; Diarrhea; Injections, Intraventricular; Injections, Spinal; Male; Membranes; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Pyrazoles; Rats; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spinal Cord; Sulfoxides

Involvement of supraspinal and spinal mu opioid receptors in the development degree of morphine dependence was estimated by the ED50 values of naloxone (s.c.) required to precipitate withdrawal jumping and diarrhea 72 hr after morphine-pellet implantation. beta-FNA was administered 4 times (24 hr before, just before, 24 and 48 hr after morphine-pellet implantation) by the i.c.v. or i.t. route. beta-FNA (both i.c.v. and i.t. routes) significantly increased the ED50 values of naloxone for jumping and diarrhea and the increase in the ED50 value of naloxone for jumping was much greater than that for diarrhea. I.c.v. administered beta-FNA was more potent in increasing the ED50 value of naloxone for jumping than i.t. administered beta-FNA. On the other hand, i.c.v. administered beta-FNA was equipotent with i.t. administered beta-FNA in increasing the ED50 value of naloxone for diarrhea. These results suggest that both supraspinal and spinal mu opioid receptors are involved in the development of morphine dependence and that supraspinal mu receptors play a more important role than spinal mu receptors in withdrawal jumping which may reflect an excitation of the central nervous system whereas supraspinal and spinal mu receptors have similar importance in withdrawal diarrhea which may reflect an abnormal function of the autonomic nervous system.

Topics: Animals; Brain; Cerebral Ventricles; Diarrhea; Injections, Intraventricular; Injections, Spinal; Male; Mice; Morphine Dependence; Motor Activity; Naloxone; Naltrexone; Narcotic Antagonists; Receptors, Opioid, mu; Spinal Cord; Substance Withdrawal Syndrome