González-Rodríguez Sara, Quadir Mohiuddin A, Gupta Shilpi, Walker Karolina A, Zhang Xuejiao, Spahn Viola, Labuz Dominika, Rodriguez-Gaztelumendi Antonio, Schmelz Martin, Joseph Jan, Parr Maria K, Machelska Halina, Haag Rainer, Stein Christoph
Department of Anesthesiology and Critical Care Medicine, Charité Campus Benjamin Franklin, Freie Universität Berlin, Berlin, Germany.
Helmholtz Virtual Institute Multifunctional Biomaterials for Medicine, Teltow, Germany.
Elife. 2017 Jul 4;6:e27081. doi: 10.7554/eLife.27081.
Novel painkillers are urgently needed. The activation of opioid receptors in peripheral inflamed tissue can reduce pain without central adverse effects such as sedation, apnoea, or addiction. Here, we use an unprecedented strategy and report the synthesis and analgesic efficacy of the standard opioid morphine covalently attached to hyperbranched polyglycerol (PG-M) by a cleavable linker. With its high-molecular weight and hydrophilicity, this conjugate is designed to selectively release morphine in injured tissue and to prevent blood-brain barrier permeation. In contrast to conventional morphine, intravenous PG-M exclusively activated peripheral opioid receptors to produce analgesia in inflamed rat paws without major side effects such as sedation or constipation. Concentrations of morphine in the brain, blood, paw tissue, and in vitro confirmed the selective release of morphine in the inflamed milieu. Thus, PG-M may serve as prototype of a peripherally restricted opioid formulation designed to forego central and intestinal side effects.
新型止痛药亟待研发。激活外周炎症组织中的阿片受体可减轻疼痛，且无镇静、呼吸暂停或成瘾等中枢不良反应。在此，我们采用了一种前所未有的策略，报告了通过可裂解连接子将标准阿片类药物吗啡共价连接到超支化聚甘油（PG-M）上的合成方法及镇痛效果。这种缀合物具有高分子量和亲水性，旨在选择性地在损伤组织中释放吗啡，并防止其透过血脑屏障。与传统吗啡不同，静脉注射PG-M仅激活外周阿片受体，从而在炎症大鼠爪中产生镇痛作用，而无镇静或便秘等主要副作用。大脑、血液、爪组织中的吗啡浓度以及体外实验均证实了吗啡在炎症环境中的选择性释放。因此，PG-M可作为一种外周受限阿片制剂的原型，旨在避免中枢和肠道副作用。
