Lack of involvement of type 7 phosphodiesterase in an experimental model of asthma.

Type 7 phosphodiesterases (PDE7) are responsible for the decrease of intracellular cyclic AMP (cAMP) in many cells involved in allergic asthma by suppressing their potential to respond to many activating stimuli. The elevation of intracellular cAMP has been associated with immunosuppressive and anti-inflammatory activities and represents a potential treatment of asthma. Our aim was to evaluate the impact of the deletion of the murine phosphodiesterase (PDE)7B gene and then to evaluate the efficacy of a newly described selective PDE7A and -B inhibitor on an ovalbumin (OVA)-induced airway inflammation and airway hyperreactivity (AHR) model in mice. Inflammation was determined 72 h after single OVA challenge or 24 h after multiple challenges by the relative cell influx and cytokine content in bronchoalveolar lavage fluid. AHR and immunoglobulin E levels in serum were determined after multiple challenges. For the first time, we have demonstrated that the deletion of the PDE7B gene or the pharmacological inhibition of PDE7A and -B had no effect on all the parameters looked at in this model. These results highlight the absence of any implication of the PDE7 enzyme in our model.

Antidiarrhoeal properties of a novel sigma ligand (JO 2871) on toxigenic diarrhoea in mice: mechanisms of action.

BACKGROUND AND AIMS: Sigma ligands display antisecretory activity against various secretagogues, suggesting antidiarrhoeal properties. In this study, we evaluated: (i) the antidiarrhoeal effect of JO 2871, a high affinity sigma ligand, in three models of toxigenic diarrhoea in mice; and (ii) the site and mechanism of action of this compound. METHODS: Faeces were collected after toxin or vehicle administration in male DBA2 or NMRI mice. Diarrhoea was determined by cumulative stool weight (mg) over a 120 minute period. Diarrhoea was induced by intravenous administration of Salmonella enteriditis lipopolysaccharide (LPS), or oral administration of Escherichia coli heat stable (E coli-sta) or Clostridium difficile toxins. Two sigma ligands, igmesine and JO 2871, were administered either orally or intravenously, 60 and 30 minutes before the toxins, respectively. JO 2871 was also given orally 30 minutes after E coli-sta. In addition, JO 2871 was administered intracerebroventricularly five minutes before LPS and E coli-sta. BMY 14802 (1000 microg/kg orally), a sigma receptor antagonist, or cyclosomatostatin (CSS 1 microg/kg intravenously), a somatostatin antagonist, were given five minutes prior to JO 2871 in LPS, E coli-sta, and C difficile toxin treated mice. Gastric emptying and intestinal transit were evaluated after oral JO 2871 and BMY 14802 and intravenous CSS. RESULTS: Stool weight measured 120 minutes after administration of the toxins was significantly increased. Oral JO 2871 and igmesine dose dependently inhibited toxigenic diarrhoea in all models. ED(50) values obtained using JO 2871 (1-20 microg/kg) were more than 40 times lower than those obtained with igmesine. Oral JO 2871 given after E coli-sta also inhibited diarrhoea in a dose dependent manner (ED(50) 50 microg/kg). Both sigma ligands were active by the intravenous route on LPS and E coli-sta induced stool weight increases. JO 2871 administered intracerebroventricularly failed to block this effect at any dose tested. Both BMY 14802 and CSS reversed the antidiarrhoeal effect of oral JO 2871. JO 2871, BMY 14802, and CSS did not affect transit parameters. CONCLUSIONS: JO 2871 exerts a potent oral antidiarrhoeal effect, acting peripherally through sigma sites and somatostatin release.

Role of vagal afferents in the antinociception produced by morphine and U-50,488H in the colonic pain reflex in rats.

The mechanisms underlying the antinociception induced by morphine or U-50,488H (trans-(+-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]- cyclohexyl)benzeneacetamide) against painful colonic distension were examined in anaesthetized rats. The respective ED50 values for morphine and U-50,488H were 0.34 and 0.35 mg/kg for the i.v. route, and 1.68 and 167 micrograms/rat for the i.c.v. route. Morphine was active by the intrathecal route (ED50 = 7.8 micrograms) whereas U-50,488H had no effect at doses up to 100 micrograms/rat. The morphine response was selectively antagonized by naloxone (30 micrograms/kg i.v.) whereas that of U-50,488H was blocked by nor-binaltorphimine (10 mg/kg s.c.). Bilateral vagotomy abolished the response to morphine at 0.35 mg/kg i.v. and reduced by 41.3% that to 1 mg/kg morphine, but had no effect on that to U-50,488H or i.c.v. morphine (10 micrograms/rat). It is concluded that peripheral mu- and kappa-opioid receptors may produce antinociception for colonic pain and that vagal integrity is required for mu-opioid but not kappa-opioid peripheral antinociception.