Intracerebroventricular injection of a TRH analogue, gamma-butyrolactone-gamma-carbonyl-L-histidyl-prolinamide, induces gastric lesions and gastric acid stimulation in rats

Abstract

The effects of TRH and its biologically stable analogue, gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide (DN-1417), on gastric mucosa and acid secretion were examined in rats. Intracerebroventricular (ICV) injection of DN-1417 (0.1-10 micrograms) caused a dose-dependent gastric lesion in the corpus and antrum 6 h after administration. The gastric lesions produced by 1 microgram of DN-1417 were more severe than those produced by ICV TRH (10 micrograms), intravenous DN-1417 (200 micrograms) and stress. Although the lesion-generating effect of TRH (10 micrograms) tended to be reduced 6 h after the injection, that of DN-1417 (1 microgram) was sustained during 6 h. Atropine (0.1 and 1 mg/kg s.c.) inhibited DN-1417-induced gastric lesions in a dose-related manner while sulpiride (10 and 30 mg/kg s.c.), haloperidol (1 mg/kg i.p.), phentolamine (1 and 5 mg/kg s.c.) and yohimbine (5 mg/kg s.c.) did not prevent the lesions. ICV DN-1417 also stimulated basal gastric acid secretion and the effect was stronger and longer-lasting than that of TRH. Atropine (0.1 mg/kg s.c.) stopped DN-1417-stimulated gastric acid secretion. In conclusion, the possibility that TRH may be involved in the CNS modulation of gastric mucosal integrity deserves further attention. The enhanced potency of action of DN-1417 over TRH could make ICV injection of this peptide a useful tool for inducing centrally-mediated gastric lesions in rats.