Suppression of vagus‐mediated pancreatic polypeptide release by the μ‐opiate receptor agonist loperamide in man

Abstract

1Morphine suppresses the release of pancreatic polypeptide, a hormone under vagal cholinergic control. The intention of the study was to detect whether the μ‐opiate receptor agonist loperamide is also able to inhibit pancreatic polypeptide release, and to define its site of action. 2In groups of healthy subjects (n=6 each) stimulation of pancreatic polypeptide was assessed in five different tests: (i) insulin‐hypoglycaemia; (ii) modified sham feeding; (iii) intravenous infusion of the cholecystokinin analogue ceruletide; (iv) injection of corticotropin releasing hormone; (v) infusion of the muscarinic acetylcholine agonist bethanechol. All tests were performed after oral application of either a placebo or loperamide (16 mg), tests (ii) and (iii) were repeated with loperamide in smaller doses (2 and 6 mg), with loperamide plus naloxone, with naloxone alone, and with infusion of atropine. Plasma concentrations of pancreatic polypeptide were measured radioimmunologically. 3Release of pancreatic polypeptide in test (i) to (iv) was completely blocked by 16 mg loperamide, whereas bethanechol‐stimulated release (test 5) was not influenced. Tests (ii) and (iii) showed that the inhibition was dose‐dependent and could be attenuated by naloxone. The inhibitory effect of loperamide was comparable with that of atropine. 4We conclude that loperamide causes a dose‐dependent inhibition of pancreatic polypeptide release mediated by vagal‐cholinergic pathways, but does not have an atropine‐like peripheral action.

Loperamide-Induced Acute Pancreatitis

“…The effect on diarrhea is primarily due to an inhibition of intestinal secretion and gut motility [10]. The mechanism of pancreatic injury is thought to be by two different mechanisms.…”

“…Being an opiate it probably causes a spasm at the sphincter of Oddi in a similar waytomorphine. A study on 6 healthy people has shown that loperamide causes dose-dependent inhibition of pancreatic polypeptide release mediated by vagal-cholinergic pathways [10]. The pancreatic polypeptide suppresses the secretion from exocrine pancreas, and it has been proposed that it most likely increases exocrine pancreas secretion [9].…”

μ‐Opiate receptor agonist loperamide blocks bethanechol‐induced gallbladder contraction, despite higher cholecystokinin plasma levels in man

“…11 The l-opiate receptor agonist loperamide blocked bethanechol-induced gallbladder contraction in the current study, and it has previously been shown to inhibit CCK-induced gallbladder contraction in humans. 5 A direct effect of opiate peptides -mediated by opiate receptors -on pancreatic cells was excluded. 22 The findings reported here are consistent with the results of Guarraci et al 11 showing that opioid agonists have a potent inhibitory effect on gallbladder motility by decreasing the release of Ach and other excitatory neurotransmitters in guinea-pigs.…”

“…Consistent with our present results demonstrating a loperamide-mediated decrease in neurally mediated gallbladder emptying, we described a loperamide-mediated inhibition of vagal function after corticotrophin-releasing hormone (CRH) injection, modified sham-feeding and insulin hypoglycaemia testing, while peripheral atropine-like cholinergic actions, like PP release upon bethanechol infusion, were unaffected. 5 A direct effect of opiate peptides -mediated by opiate receptors -on pancreatic cells was excluded. 26 An influence of loperamide on vagal afferents cannot be excluded, as l-opiate receptors have been detected in presynaptical parts of vagal afferents 27 and mesenteric afferent fibres are markedly stimulated by l-opioid receptor agonists -an effect blocked by l-opiate antagonist alvimopan.…”

“…In contrast, peripheral cholinergic actions, like PP release after bethanechol infusion (muscarinergic agonist), were unaffected. 5 Opioids suppress intestinal secretion of water and electrolytes and attenuate the transport of bile into the duodenum. 6 The l-opiate receptor agonist, loperamide suppresses cholecystokinin (CCK)-induced gallbladder contractions in a dose-dependent manner, 7,8 and basal and amino acid-stimulated gallbladder motility, intraduodenal output of bilirubin and amylase 9 and biliary excretion.…”