Supraspinal delta- and mu-opioid receptors mediate gastric mucosal protection in the rat

This study evaluated the contribution of supraspinal opioid receptors to ga stric mucosal protection in the rat. Intracerebroventricular (i.c.v.) and i ntracisternal (i.c.) injections of selective delta- ([D-Ala(2),D-Leu(5)]-en kephalin (DADLE), [D-Pen(2),D-Pen(5)]-enkephalin (DPDPE), deltorphin II), s elective mu- ([D-Ala(2),Phe(4),Gly(5)-ol]-enkephalin (DAGO)) opioid recepto r agonists and beta -endorphin (ligand of both receptor types) produced a d ose-dependent inhibition of acidified ethanol-induced gastric mucosal damag e. The ED50 values for beta -endorphin, DAGO, DADLE, deltorphin II, and DPD PE 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 gast roprotective effect of DADLE, deltorphin II, and DPDPE, but not that of DAG O, was inhibited by naltrindole, the selective delta -receptor antagonist. Since the delta (2)-receptor agonist deltorphin II was more potent than the delta (1)-receptor agonist DPDPE, the dominant role of central delta (2)-r eceptors in gastroprotection might be raised. The site of action for delta -receptor agonists is likely to be the brain stem since the peptides were m ore potent following i.c. than following i.c.v. administration. The gastrop rotective effect was reduced following acute bilateral cervical vagotomy. M oreover, both the nitric-oxide synthase inhibitor N-G-nitro-L-arginine (3 m g/kg i.v.) and the prostaglandin synthesis inhibitor indomethacin (20 mg/kg p.o.) decreased the protective effect of opioid peptides. The results indi cate that 1) activation of supraspinal delta- and mu -opiold receptors indu ces gastric mucosal protection, 2) integrity of vagal nerve is necessary fo r the gastroprotective action of opioids, and 3) mucosal nitric oxide and p rostaglandins may be involved in the opioid-induced gastroprotection.