Broccardo M, Linari G, Guerrini R, Agostini S, Petrella C, Improta G
Department of Human Physiology and Pharmacology, University of Rome La Sapienza, Ple A. Moro 5-00185 Rome, Italy.
Peptides. 2005 Sep;26(9):1590-7. doi: 10.1016/j.peptides.2005.02.018. Epub 2005 Mar 19.
Nociceptin/orphanin FQ (N/OFQ) administered into the lateral left cerebral ventricle of rats has been reported to inhibit in vivo gut motor and secretory functions. Recently, a novel N/OFQ analog, [Arg14, Lys15] N/OFQ, was synthesized and demonstrated to behave as a highly potent agonist at the human recombinant N/OFQ peptide (NOP) receptors and to produce long-lasting effects in vivo in mice compared with the natural ligand N/OFQ. In the present study, the pharmacological profile of [Arg14, Lys15] N/OFQ was further evaluated and compared with that of N/OFQ in vitro on guinea pig exocrine pancreas and in vivo on gastric emptying, colonic propulsion and gastric acid secretion in rats. [Arg14, Lys15] N/OFQ and N/OFQ significantly decreased the KCl-evoked amylase secretion from isolated pancreatic lobules of the guinea pig. In in vivo experiments, [Arg14, Lys15] N/OFQ mimicked the effects of N/OFQ, inducing, after intracerebroventricular injection, a delay (up to 70%) in the gastric emptying of a phenol red meal, an increase (about 40 times) of the mean bead colonic expulsion time and a decrease (up to 90%) of gastric acid secretion in water loaded rats after 90 min pylorus ligature. In all these assays, [Arg14, Lys15] N/OFQ was more effective than N/OFQ, and its effective doses were at least 10-fold lower than N/OFQ effective doses. The highly selective NOP receptor antagonist, UFP-101, decreased the efficacy of [Arg14, Lys15] N/OFQ in in vitro and in vivo assays above reported. These findings: (a) show that pancreatic NOP receptors mediate an in vitro inhibitory effect on stimulated guinea pig amylase secretion; (b) confirm that the stimulation of central NOP receptors exerts an inhibitory control on gastric emptying, colonic motility and gastric secretion in rats and (c) put in evidence that [Arg14, Lys15] N/OFQ, being more potent and effective than the natural ligand N/OFQ, represents a new pharmacological tool for the study of the physiological and pharmacological roles mediated by the N/OFQ-NOP receptor system.
据报道，向大鼠左侧侧脑室注射痛敏肽/孤啡肽FQ（N/OFQ）可抑制体内肠道运动和分泌功能。最近，一种新型的N/OFQ类似物[精氨酸14，赖氨酸15]N/OFQ被合成出来，它在人重组N/OFQ肽（NOP）受体上表现为高效激动剂，与天然配体N/OFQ相比，在小鼠体内能产生持久的效应。在本研究中，进一步评估了[精氨酸14，赖氨酸15]N/OFQ的药理学特性，并在体外对豚鼠外分泌胰腺以及在体内对大鼠的胃排空、结肠推进和胃酸分泌方面与N/OFQ进行了比较。[精氨酸14，赖氨酸15]N/OFQ和N/OFQ显著降低了豚鼠离体胰腺小叶中由氯化钾诱发的淀粉酶分泌。在体内实验中，[精氨酸14，赖氨酸15]N/OFQ模拟了N/OFQ的作用，脑室内注射后，导致酚红餐胃排空延迟（高达70%），平均珠子结肠排出时间增加（约40倍），在幽门结扎90分钟后的水负荷大鼠中胃酸分泌减少（高达90%）。在所有这些实验中，[精氨酸14，赖氨酸15]N/OFQ比N/OFQ更有效，其有效剂量比N/OFQ的有效剂量至少低10倍。高度选择性的NOP受体拮抗剂UFP-101降低了[精氨酸14，赖氨酸15]N/OFQ在上述体外和体内实验中的效能。这些发现：（a）表明胰腺NOP受体介导了对豚鼠淀粉酶分泌刺激的体外抑制作用；（b）证实中枢NOP受体的刺激对大鼠的胃排空、结肠运动和胃分泌施加了抑制性控制；以及（c）证明[精氨酸14，赖氨酸15]N/OFQ比天然配体N/OFQ更有效且效力更强，是研究由N/OFQ-NOP受体系统介导的生理和药理作用的一种新的药理学工具。
