Institute of Biochemistry and Molecular Biology, Lanzhou University, Lanzhou 730000, China.
Peptides. 2011 Feb;32(2):293-9. doi: 10.1016/j.peptides.2010.10.024. Epub 2010 Nov 3.
Endomorphins (EMs) cannot be delivered into the central nervous system (CNS) in sufficient quantity to elicit antinociception when given systemically because they are severely restricted by the blood-brain barrier (BBB). In the present study, we investigated herein a series of EM-1 analogs with C-terminal linked by oligoarginine in order to improve the brain delivery and antinociception after systemic administration. Indeed, all these analogs decreased the opioid receptor affinity and in vitro pharmacological activity. Moreover, analogs 4, 7-9 produced a less potent antinociceptive activity after intracerebroventricular (i.c.v.) administration, with the ED(50) values about 11- to 13-fold lower potencies than that of EM-1. Nevertheless, our results revealed that EM-1 failed to induce any significant antinociception at a dose of 50μmol/kg after subcutaneous (s.c.) administration, whereas equimolar dose of these four analogs produced a little low but significant antinociceptive effects. Naloxone (10nmol/kg, i.c.v.) significantly blocked the antinociceptive effects, indicating an opioid and central mechanism. These results demonstrated that C-terminal of EM-1 linked to oligoarginine improved the brain delivery, eliciting potent antinociception following peripheral administration.
内吗啡肽（Endomorphins，EMs）不能以足够的数量递送至中枢神经系统（Central Nervous System，CNS）以产生抗伤害感受作用，因为它们受到血脑屏障（Blood-Brain Barrier，BBB）的严重限制。在本研究中，我们研究了一系列通过寡精氨酸连接的 C 末端的 EM-1 类似物，以改善系统给药后的脑内传递和抗伤害感受作用。事实上，所有这些类似物均降低了阿片受体亲和力和体外药理学活性。此外，类似物 4、7-9 在侧脑室（Intracerebroventricular，i.c.v.）给药后产生的抗伤害感受活性较弱，ED50 值比 EM-1 低约 11-13 倍。然而，我们的结果表明，EM-1 在皮下（Subcutaneous，s.c.）给药 50μmol/kg 的剂量下未能诱导任何显著的抗伤害感受作用，而这四个类似物的等摩尔剂量产生了稍微低但有统计学意义的抗伤害感受作用。纳洛酮（10nmol/kg，i.c.v.）显著阻断了抗伤害感受作用，表明存在阿片类和中枢机制。这些结果表明，EM-1 的 C 末端与寡精氨酸连接可改善脑内传递，在周围给药后可引发有效的抗伤害感受作用。
