THE INHIBITORY EFFECTS OF ALPHA(2)-ADRENOCEPTOR AGONISTS ON GASTROINTESTINAL TRANSIT DURING CROTON OIL-INDUCED INTESTINAL INFLAMMATION

1 The peripheral effects of az-adrenoceptor agonists were investigated in a model of intestinal inflammation induced by intragastric adminis tration of croton oil (GO). Our hypothesis was that inflammation would 'sensitize' adrenoceptors in peripheral and/or central terminals of m yenteric and submucous plexus neurones, and enhance systemic effects o f alpha(2)-adrenoceptor agonists. 2 Male swiss CD-1 mice, received int ragastrically 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 ass essed by electron microscopy. 3 The intragastric administration of CA or CO caused an increase in GIT and weight loss, but only CO induced a n inflammatory response. Both clonidine (imidazoline(1)/alpha(2)-agoni st) and UK-14304 (alpha(2)-agonist) produced dose-related inhibitions of GIT in all groups. During inflammatory diarrhoea (GO), 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 an tagonists, 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 th e potency of i.c.v. clonidine, demonstrating that enhanced effects of s.c. clonidine are mediated by peripheral receptors. During inflammati on, i.c.v. efaroxan did not antagonize low doses of s.c. clonidine (ED (20) and ED(50)s), but partially reversed ED(80)s, further supporting the peripheral effects of the agonists in CO treated animals. 5 The re sults 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 receptor s.