Tonini M, Fiori E, Balestra B, Spelta V, D'Agostino G, Di Nucci A, Brecha N C, Sternini C
Department of Internal Medicine and Therapeutics, University of Pavia, Italy.
Naunyn Schmiedebergs Arch Pharmacol. 1998 Dec;358(6):686-9. doi: 10.1007/pl00005313.
The novel opioid tetrapeptides, endomorphin-1 and endomorphin-2, recently isolated from bovine and human brain bind with high affinity and selectivity to central mu-opioid receptors. In the digestive tract, a comprehensive pharmacological analysis of the receptors involved in endomorphin action has not been reported. In this study, we analyzed the effects of endomorphin-1 and endomorphin-2 on longitudinal muscle-myenteric plexus preparations (LMMPs) from the guinea-pig ileum. Both peptides (30 pM - 1 microM) inhibited (-log EC50 values: 8.61 and 8.59, respectively) the amplitude of electrically-induced twitch contractions in a concentration-dependent fashion, up to its abolition. Conversely, in unstimulated LMMPs, they failed to affect contractions to applied acetylcholine (100 nM). In stimulated LMMPs, the highly selective mu-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), caused a concentration-dependent (30 nM-1 microM), parallel rightward shift of endomorphin-1 and endomorphin-2 inhibitory curves, without depression of their maximum. Following Schild analysis, calculated pA2 values were 7.81 and 7.85, respectively, with slopes not different from unity. Concentration-response curves to both peptides were not affected by 30 nM naltrindole (a selective delta-receptor antagonist) or 30 nM nor-binaltorphimine (a selective kappa-receptor antagonist). These results demonstrate that endomorphins selectively activate mu-opioid receptors located on excitatory myenteric plexus neurons, and that they act as full agonists.
最近从牛和人脑中分离出的新型阿片样物质四肽内吗啡肽-1和内吗啡肽-2，能以高亲和力和选择性与中枢μ-阿片受体结合。在消化道中，尚未见有关内吗啡肽作用所涉及受体的全面药理学分析报道。在本研究中，我们分析了内吗啡肽-1和内吗啡肽-2对豚鼠回肠纵行肌-肌间神经丛标本（LMMPs）的作用。两种肽（30 pM - 1 μM）均以浓度依赖性方式抑制（-log EC50值分别为8.61和8.59）电诱导的抽搐收缩幅度，直至收缩完全消失。相反，在未受刺激的LMMPs中，它们未能影响对所施加乙酰胆碱（100 nM）的收缩反应。在受刺激的LMMPs中，高选择性的μ-阿片受体拮抗剂D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2（CTOP）引起内吗啡肽-1和内吗啡肽-2抑制曲线浓度依赖性（30 nM - 1 μM）的平行右移，但其最大抑制作用未受影响。根据Schild分析，计算出的pA2值分别为7.81和7.85，斜率与1无差异。两种肽的浓度-反应曲线不受30 nM纳曲吲哚（一种选择性δ受体拮抗剂）或30 nM去甲二氢吗啡酮（一种选择性κ受体拮抗剂）的影响。这些结果表明，内吗啡肽选择性激活位于兴奋性肌间神经丛神经元上的μ-阿片受体，并且它们作为完全激动剂发挥作用。
