Loperamide-induced inhibition of pancreatic secretion in rats

The effects of loperamide on exocrine pancreatic secretion were studied in rats fitted with chronic or acute fistulas. Intraduodenal injection of loperamide in conscious rats resulted in a dose-dependent inhibition of basal pancreatic secretion involving volume and bicarbonate and protein output with an ED50 of about 0.5 mg/kg. The maximal inhibition observed was about 60% for volume and bicarbonate output and 90% for protein output. Loperamide induced an inhibition of pancreatic secretion in conscious rats that was naloxone-sensitive and persisted in cimetidine-treated rats. Thus, it did not depend on modifications of gastric secretion. In anaesthetized rats, loperamide did not inhibit the pancreatic secretion evoked by agents acting directly on the pancreatic cells (acetylcholine, secretin, CCK) but it inhibited by 100% the pancreatic secretion induced by vagal electrical stimulation (VES) and by 80-100% that induced by 5 thio-glucose, a centrally acting vagal stimulatory agent. Loperamide inhibition of VES-induced pancreatic secretion was different from that obtained with morphine or methadone since these opiate drugs could only inhibit by 50-60% maximally the VES-stimulated pancreatic secretion. The loperamide inhibition of VES-induced secretion was naloxone-insensitive, while loperamide inhibition of 5 thio-glucose-induced secretion was in part naloxone-sensitive. These results suggest that loperamide exerts a potent inhibition of pancreatic secretion by acting on the nerve supply to the pancreas through both opiate and non-opiate mechanisms.