Central thyrotropin-releasing factor analog prevents ethanol-induced gastric damage through prostaglandins in rats

The effects of intracisternal injection of the stable thyrotropin-releasing factor (TRH) analog RX 77368 on gastric lesions induced by 60% ethanol and gastric prostaglandin E2 (PGE2) release were studied in rats. RX 77368 (1.0 and 1.5 ng) injected intracisternally inhibited (by 58% and 78%, respectively) macroscopic gastric damage induced by ethanol. Higher doses (3 and 300 ng) inhibited ethanol-induced gastric injury only in rats pretreated with omeprazole (20 mg/kg SC). Gastric acid output measured in conscious rats 2 hours after pylorus ligation was not modified by intracisternal injection of RX 77368 at 1.5 ng but was significantly increased by 54% at the 3-ng dose. The protective effect of TRH analog (1.5 ng) was completely abolished by indomethacin (5 mg/kg IP) and atropine (2 mg/kg SC) pretreatment. In pylorus-ligated rats, intracisternal RX 77368 (1.5 ng) inhibited ethanol-induced gastric lesions by 64%. Intracisternal injection of RX 77368 (1.5 ng) increased PGE2 levels measured in the effluent of dialysis fibers implanted into the corpus submucosa of urethane-anesthetized rats. Peripheral administration of omeprazole, atropine, indomethacin, or RX 77368 (1.5 ng IV) did not influence gastric damage induced by ethanol. These data show that the stable TRH analog, RX 77368, injected intracisternally at low non-secretory doses acts in the brain to protect against ethanol lesions through prostaglandin and cholinergic pathways. These findings suggest that central vagal activation induced by TRH may play a role in the control of mucosal integrity against ethanol through cholinergic prostaglandin release.