title: The inhibitory effects of alpha(2)-adrenoceptor agonists on gastrointestinal transit during croton oil-induced intestinal inflammation.
abstract: 1. The peripheral effects of alpha(2)-adrenoceptor agonists were investigated in a model of intestinal inflammation induced by intragastric administration of croton oil (CO). Our hypothesis was that inflammation would 'sensitize' adrenoceptors in peripheral and/or central terminals of myenteric and submucous plexus neurones, and enhance systemic effects of alpha(2)-adrenoceptor agonists. 2. Male swiss CD-1 mice, received intragastrically CO (0.05 ml), castor oil (CA, 0.1 ml) or saline (SS) 3 h before the study: gastrointestinal transit (GIT) was evaluated 20 min afterwards with a charcoal meal. The presence of inflammation was assessed by electron microscopy. 3. The intragastric administration of CA or CO caused an increase in GIT and weight loss, but only CO induced an inflammatory response. Both clonidine (imidazoline1/alpha(2)-agonist) and UK-14304 (alpha(2)-agonist) produced dose-related inhibitions of GIT in all groups. During inflammatory diarrhoea (CO), potencies of systemic (s.c.) clonidine and UK-14304 were significantly increased 3.5 and 2.1 times, respectively, while potencies remained unaltered in the presence of diarrhoea without inflammation (CA). The effects were reversed by administration (s.c.) of receptor-specific adrenoceptor antagonists, but not by naloxone. 4. Clonidine was 8.3 (SS) and 2.8 (CO) times more potent when administered intracerebroventricularly (i.c.v.), than when administered s.c. Inflammation of the gut did not alter the potency of i.c.v. clonidine, demonstrating that enhanced effects of s.c. clonidine are mediated by peripheral receptors. During inflammation, i.c.v. efaroxan did not antagonize low doses of s.c. clonidine (ED20 and ED50S), but partially reversed ED80S, further supporting the peripheral effects of the agonists in CO treated animals. 5. The results demonstrate that inflammation of the gut enhances the potency of alpha(2)-adrenoceptor agonists by a peripheral mechanism. The results also suggest that the inflammatory response induces an up-regulation or sensitization of alpha(2)-adrenoceptors and/or imidazoline receptors.
authors.affiliation: IMIM, Department of Anesthesiology, Hospital Universitario del Mar, Barcelona, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Pol
authors.forename: L
authors.initials: L
authors.lastname: Valle
authors.forename: I
authors.initials: I
authors.lastname: Ferrer
authors.forename: M M
authors.initials: MM
authors.lastname: Puig
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002368:Castor Oil; D003000:Clonidine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D003436:Croton Oil; D003967:Diarrhea / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D004751:Enteritis / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D005765:Gastrointestinal Agents; D005772:Gastrointestinal Transit / Q000187:drug effects*; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008854:Microscopy, Electron
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D005765:Gastrointestinal Agents; D003436:Croton Oil; D002368:Castor Oil; D003000:Clonidine