Polyglycerol-opioid conjugate produces analgesia devoid of side effects
Sara González-Rodríguez,
Mohiuddin A Quadir,
Shilpi Gupta,
Karolina A Walker,
Xuejiao Zhang,
Viola Spahn,
Dominika Labuz,
Antonio Rodriguez-Gaztelumendi,
Martin Schmelz,
Jan Joseph,
Maria K Parr,
Halina Machelska,
Rainer Haag,
Christoph Stein
Affiliations
Sara González-Rodríguez
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
Mohiuddin A Quadir
Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
Shilpi Gupta
Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
Karolina A Walker
Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
Xuejiao Zhang
Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
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
Rainer Haag
Helmholtz Virtual Institute Multifunctional Biomaterials for Medicine, Teltow, Germany; Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
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
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.
