• Norikazu Kiguchi, Huiping Ding, Gerta Cami-Kobeci, Devki D Sukhtankar, Paul W Czoty, Heather B DeLoid, Fang-Chi Hsu, Lawrence Toll, Stephen M Husbands, and Mei-Chuan Ko.
• Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA; Department of Pharmacology, Wakayama Medical University, Wakayama, Japan.
• Br J Anaesth. 2019 Jun 1; 122 (6): e146-e156.

BackgroundThe marked increase in mis-use of prescription opioids has greatly affected our society. One potential solution is to develop improved analgesics which have agonist action at both mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptors. BU10038 is a recently identified bifunctional MOP/NOP partial agonist. The aim of this study was to determine the functional profile of systemic or spinal delivery of BU10038 in primates after acute and chronic administration.MethodsA series of behavioural and physiological assays have been established specifically to reflect the therapeutic (analgesia) and side-effects (abuse potential, respiratory depression, itch, physical dependence, and tolerance) of opioid analgesics in rhesus monkeys.ResultsAfter systemic administration, BU10038 (0.001-0.01 mg kg-1) dose-dependently produced long-lasting antinociceptive and antihypersensitive effects. Unlike the MOP agonist oxycodone, BU10038 lacked reinforcing effects (i.e. little or no abuse liability), and BU10038 did not compromise the physiological functions of primates including respiration, cardiovascular activities, and body temperature at antinociceptive doses and a 10-30-fold higher dose (0.01-0.1 mg kg-1). After intrathecal administration, BU10038 (3 μg) exerted morphine-comparable antinociception and antihypersensitivity without itch scratching responses. Unlike morphine, BU10038 did not cause the development of physical dependence and tolerance after repeated and chronic administration.ConclusionsThese in vivo findings demonstrate the translational potential of bifunctional MOP/NOP receptor agonists such as BU10038 as a safe, non-addictive analgesic with fewer side-effects in primates. This study strongly supports that bifunctional MOP/NOP agonists may provide improved analgesics and an alternative solution for the ongoing prescription opioid crisis.Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

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