Effect of opiate-active substances on pancreatic polypeptide levels in dogs

The present study examines the effect of orally and intravenously administered opiate-active substances on peripheral vein plasma pancreatic polypeptide (PP) levels in conscious dogs. The intragastric instillation of digested gluten stimulated postprandial PP levels significantly which was reduced by the specific opiate-receptor antagonist naloxone. Naloxone had no effect when added to undigested gluten. Similarly, naloxone reduced significantly the postprandial PP response to a test meal of casopeptone which contains the opiate-active β-casomorphins. The addition of synthetic β-casomorphins to a liver extract/sucrose test meal significantly augmented the rise of postprandial PP levels which was also blocked by naloxone. The intravenous infusion of morphine, leu-enkephalin, D-ala²-D-leu⁵-enkephalin, β-casomorphin-5 and β-casomorphin-4 elicited a dose-dependent and naloxone reversible effect on basal PP levels. During a background infusion of glucose and amino acids the same opiate-active substances had either none or a stimulatory effect on PP release in these dogs. The addition of naloxone abolished the stimulatory effect in response to β-casomorphin-5 and β-casomorphin-4 and resulted in an inhibition of PP levels during the infusion of morphine and leu-enkephalin. This latter inhibitory effect was no longer observed when the dose of naloxone was increased ten- and fifty-fold, respectively. The present data suggest that orally ingested opiate-active substances participate in the stimulation of postprandial PP release in dogs via specific opiate-receptor mediated mechanisms. The effect of intravenously administered opiate-active substances on PP levels depends on the metabolic state with regard to the level of circulating nutrients. It is suggested that PP release is stimulated via μ-opiate receptors and inhibited via δ-opiate receptors. An increase of circulating nutrients would "activate" μ-receptor sites which are masked in the basal state when exogenous opiates are administered. However, with regard to endogenous opiates an increase of circulating nutrients, mainly carbohydrates, activates inhibitory effects of endogenous opiates suggesting that exogenous and endogenous opiates act at different target sites.