Regulation of pancreatic secretion in vitro by nociceptin/orphanin FQ and opioid receptors: A comparative study

The effects of nociceptin/orphanin FQ (N/OFQ) on gastrointestinal functions resemble those of classic analgesic opioid agonists. In this study, we compared changes in amylase release from guinea pig isolated pancreatic acini and lobules induced by the N/OFQ analogue [Arg14,Lys15]N/OFQ and by the delta-receptor opioid agonist deltorphin. Carbachol strongly stimulated amylase release from isolated acini. Both peptides left baseline and carbachol-stimulated amylase secretion from pancreatic acini unchanged. Co-incubation of KCl-stimulated lobules with [Arg14,Lys15]N/OFQ or deltorphin inhibited KCl-induced amylase release in a concentration-dependent manner. Although maximal inhibition of amylase release by [Arg14,Lys15]N/OFQ and deltorphin had similar amplitude, [Arg14,Lys15]N/OFQ was 100-fold more potent than deltorphin on a molar basis. The selective NOP-receptor antagonist [Nphe1,Arg14,Lys15]N/OFQ-NH2 (UFP-101) antagonized [Arg14,Lys15]N/OFQ-induced inhibition but left deltorphin-induced inhibition unchanged. The selective delta opiate receptor antagonist naltrindole had no effect on [Arg14,Lys15]N/OFQ inhibition but partly prevented the inhibition by deltorphin. [Arg14,Lys15]N/OFQ and deltorphin combined had no influence on each other. These findings show that [Arg14,Lys15]N/OFQ inhibits pancreatic enzyme secretion by suppressing cholinergic transmission in intralobular nerve fibers, as previously reported for opioid agents. They suggest that [Arg14,Lys15]N/OFQ inhibition of amylase release is mediated through the NOP receptor and not through the delta opioid receptor. The N/OFQ-NOP receptor system, like the delta opioid system, plays an inhibitory role in regulating exocrine pancreatic secretion.