Intracisternal PYY inhibits gastric lesions induced by ethanol in rats: role of PYY-preferring receptors?

We previously reported that intracisternal (i.c.) injection of peptide YY (PYY) and low doses of thyrotropin-releasing hormone (TRH) or TRH analog, RX 77368, increased the resistance of the gastric mucosa to ethanol injury through vagal pathways in rats. The gastroprotective effect of i.c. injection of PYY/neuropeptide NPY (NPY) agonists with differential in vitro affinity to the Y receptor subtypes was examined in urethane-anesthetized rats. Intragastric administration of ethanol (45%, 5 ml/kg) results in mucosal lesions covering 23±2% of the gastric corpus in 1 h. PYY (500 ng, i.c.) significantly reduced ethanol-induced gastric lesions by 52%. [Pro 34]PYY (PYY-preferring/Y 1/Y 5/Y 4 subtypes) injected i.c. at 50, 100, 200 or 500 ng, reduced dose dependently gastric lesions to 15.4±2.2%, 11.4±3.1%, 8.6±2.9% and 5.4±2.2%, respectively. PYY 3–36, (Y 2/Y 4 subtypes), [Leu 31, Pro 34]NPY (Y 1/Y 5), NPY (Y 3/Y 1/Y 5/Y 2) and pancreatic polypeptide (PP, Y 4) injected i.c. at 500 ng did not influence significantly ethanol-induced gastric lesions. Combined i.c. injection of RX 77368 (1 ng) and Pro 34PYY (25 ng), at sub-threshold doses given singly, reduced ethanol-induced gastric injury to 12.9±2.3% while RX 77368 (1 ng) plus PYY 3–36 (500 ng) or [Leu 31, Pro 34]NPY (25 ng) had no effect. These findings indicate that i.c. PYY-induced gastric protection against 45% ethanol is mediated by a Y receptor subtype which bears similarity with the putative PYY-preferring receptor and distinct from the currently defined Y 1/Y 5; in addition, there is a synergistic interaction between activation of this PYY-preferring receptor and i.c. TRH to increase the resistance of the gastric mucosa to injury caused by 45% ethanol.