Linari Giorgio, Agostini Simona, Broccardo Maria, Petrella Carla, Improta Giovanna
University La Sapienza, Fisiologia Umana e Farmacologia, Piazzale A. Moro 5, 00185 Roma, RM, Italy.
Pharmacol Res. 2006 Nov;54(5):356-60. doi: 10.1016/j.phrs.2006.07.007. Epub 2006 Aug 15.
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 [Arg(14),Lys(15)]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 [Arg(14),Lys(15)]N/OFQ or deltorphin inhibited KCl-induced amylase release in a concentration-dependent manner. Although maximal inhibition of amylase release by [Arg(14),Lys(15)]N/OFQ and deltorphin had similar amplitude, [Arg(14),Lys(15)]N/OFQ was 100-fold more potent than deltorphin on a molar basis. The selective NOP-receptor antagonist [Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2) (UFP-101) antagonized [Arg(14),Lys(15)]N/OFQ-induced inhibition but left deltorphin-induced inhibition unchanged. The selective delta opiate receptor antagonist naltrindole had no effect on [Arg(14),Lys(15)]N/OFQ inhibition but partly prevented the inhibition by deltorphin. [Arg(14),Lys(15)]N/OFQ and deltorphin combined had no influence on each other. These findings show that [Arg(14),Lys(15)]N/OFQ inhibits pancreatic enzyme secretion by suppressing cholinergic transmission in intralobular nerve fibers, as previously reported for opioid agents. They suggest that [Arg(14),Lys(15)]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.
痛敏肽/孤啡肽FQ（N/OFQ）对胃肠功能的影响类似于经典的镇痛阿片类激动剂。在本研究中，我们比较了N/OFQ类似物[Arg(14)，Lys(15)]N/OFQ和δ-受体阿片类激动剂强啡肽对豚鼠离体胰腺腺泡和小叶淀粉酶释放的影响。卡巴胆碱强烈刺激离体腺泡淀粉酶的释放。两种肽均未改变胰腺腺泡的基础淀粉酶分泌以及卡巴胆碱刺激的淀粉酶分泌。将[Arg(14)，Lys(15)]N/OFQ或强啡肽与KCl刺激的小叶共同孵育，可浓度依赖性地抑制KCl诱导的淀粉酶释放。尽管[Arg(14)，Lys(15)]N/OFQ和强啡肽对淀粉酶释放的最大抑制幅度相似，但按摩尔计算，[Arg(14)，Lys(15)]N/OFQ的效力比强啡肽高100倍。选择性NOP受体拮抗剂[Nphe(1)，Arg(14)，Lys(15)]N/OFQ-NH(2)（UFP-101）可拮抗[Arg(14)，Lys(15)]N/OFQ诱导的抑制作用，但对强啡肽诱导的抑制作用无影响。选择性δ阿片受体拮抗剂纳曲吲哚对[Arg(14)，Lys(15)]N/OFQ的抑制作用无影响，但部分阻止了强啡肽的抑制作用。[Arg(14)，Lys(15)]N/OFQ和强啡肽联合使用对彼此无影响。这些发现表明，[Arg(14)，Lys(15)]N/OFQ通过抑制小叶内神经纤维中的胆碱能传递来抑制胰腺酶分泌，正如先前对阿片类药物的报道。它们表明，[Arg(14)，Lys(15)]N/OFQ对淀粉酶释放的抑制作用是通过NOP受体介导的，而不是通过δ阿片受体介导的。N/OFQ-NOP受体系统与δ阿片系统一样，在调节胰腺外分泌中起抑制作用。
