Abstract

This study evaluated the contribution of supraspinal opioid receptors to gastric mucosal protection in the rat. Intracerebroventricular (i.c.v.) and intracisternal (i.c.) injections of selective δ- {[d-Ala²,d-Leu⁵]-enkephalin (DADLE), [d-Pen²,d-Pen⁵]-enkephalin (DPDPE), deltorphin II}, selective μ- {[d-Ala²,Phe⁴,Gly⁵-ol]-enkephalin (DAGO)} opioid receptor agonists and β-endorphin (ligand of both receptor types) produced a dose-dependent inhibition of acidified ethanol-induced gastric mucosal damage. The ED₅₀ values for β-endorphin, DAGO, DADLE, deltorphin II, and DPDPE were 3.5, 6.8, 75, 120, and 1100 pmol/rat, respectively, following i.c.v. and 0.8, 9.0, 45, 0.25, and 7 pmol/rat following i.c. injection. The gastroprotective effect of DADLE, deltorphin II, and DPDPE, but not that of DAGO, was inhibited by naltrindole, the selective δ-receptor antagonist. Since the δ₂-receptor agonist deltorphin II was more potent than the δ₁-receptor agonist DPDPE, the dominant role of central δ₂-receptors in gastroprotection might be raised. The site of action for δ-receptor agonists is likely to be the brain stem since the peptides were more potent following i.c. than following i.c.v. administration. The gastroprotective effect was reduced following acute bilateral cervical vagotomy. Moreover, both the nitric-oxide synthase inhibitorN^G-nitro-l-arginine (3 mg/kg i.v.) and the prostaglandin synthesis inhibitor indomethacin (20 mg/kg p.o.) decreased the protective effect of opioid peptides. The results indicate that 1) activation of supraspinal δ- and μ-opioid receptors induces gastric mucosal protection, 2) integrity of vagal nerve is necessary for the gastroprotective action of opioids, and 3) mucosal nitric oxide and prostaglandins may be involved in the opioid-induced gastroprotection.