PRETREATMENT WITH SR48692 HAS DIFFERENT EFFECTS ON CENTRAL NEUROTENSIN-INDUCED GASTRIC-MUCOSAL DEFENSE AND INHIBITION OF GASTRIC-ACID SECRETION IN RATS

Neurotensin is a tridecapeptide present in the brain and gastrointesti nal tract. Administration of neurotensin into the brain results in res ponses in the gastrointestinal tract, suggesting a role for neurotensi n in the interrelationships that comprise the brain-gut axis. Intracel ebroventricular (i.c.v.) administration of neurotensin protects the ga stric mucosa against injury caused by cold water restraint (CWR) and a lso inhibits gastrin-stimulated gastric acid secretion. The hypothesis tested was that these two actions of neurotensin are mediated via its high-affinity receptor. Rats were given neurotensin (60 mu g, i.c.v.) prior to CWR or pylorus ligation after pretreatment with SR48692, a n onpeptide antagonist of the high-affinity neurotensin receptor (0.25 o r 2.5 mu g, i.c.v., or 10, 100, or 500 mu g kg(-1) i.p.). Neurotensin reduced cold water restraint (CWR)-induced gastric mucosal injury and inhibited gastrin-stimulated acid secretion. Pretreatment with SR48692 (2.5 mu g, i.c.v., or 100 mu g kg(-1), i.p.) prior to CWR blocked neu rotensin's protection of the gastric mucosa against injury. In contras t, pretreatment with 2.5 mu g SR48692, i.c.v., did not block neurotens in-induced inhibition of acid secretion, whereas 500 mu g kg(-1), i.p. , partially blocked the inhibition. SR48692 (2.5 mu g, i.c.v.) inhibit ed acid secretion, suggesting that SR48692 has agonist activity in thi s system. These results suggest that central neurotensin protects the gastric mucosa against CWR-induced injury via its high-affinity recept or. The receptor that mediates central neurotensin-induced inhibition of gastric acid secretion does not appear to be the high-affinity rece ptor since the neurotensin receptor antagonist SR48692, when given i.c .v., had agonist activity, inhibiting stimulated acid secretion. High- affinity neurotensin receptors in the periphery appear to play a role in inhibition of stimulated gastric acid secretion. (C) 1998 Elsevier Science B.V. All rights reserved.