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 inhibitorNG-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.
Footnotes
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Send reprint requests to: Dr. Klara Gyires, Semmelweis University, Faculty of Medicine, Department of Pharmacology and Pharmacotherapy, Budapest, 1089. Nagyvárad tér. 4., Hungary. E-mail: Gyirkla{at}NET.SOTE.HU
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This work was supported by Grants OTKA 032607 from the Hungarian National Research Foundation and ETT 19/2000 from the Scientific Health Council.
- Abbreviations:
- l-NNA
- NG-nitro-l-arginine
- DAGO
- [d-Ala2,Phe4,Gly5-ol]-enkephalin
- DADLE
- [d-Ala2,d-Leu5]-enkephalin
- DPDPE
- [d-Pen2,Pen5]-enkephalin
- i.c.
- intracisternal
- NO
- nitric oxide
- PG
- prostaglandin
- Received October 23, 2000.
- Accepted February 12, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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