BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates

Norikazu Kiguchi, Huiping Ding, Gerta Cami-Kobeci, Devki D. Sukhtankar, Paul W. Czoty, Heather B. DeLoid, Fang Chi Hsu, Lawrence Toll, Stephen M. Husbands, Mei Chuan Ko

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    Background: The 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. Methods: A 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. Results: After 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. Conclusions: These 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.

    Original languageEnglish
    Pages (from-to)e146–e156
    Number of pages10
    JournalBritish Journal of Anaesthesia
    Issue number6
    Early online date1 Mar 2019
    Publication statusPublished - 1 Jun 2019


    • analgesics
    • opiate addiction
    • opioid
    • opioid-related disorders
    • respiration
    • rhesus macaque
    • Injections, Spinal
    • Drug Tolerance
    • Male
    • Macaca mulatta
    • Dose-Response Relationship, Drug
    • Nociception/drug effects
    • Pain Threshold/drug effects
    • Animals
    • Hyperalgesia/drug therapy
    • Drug Evaluation, Preclinical/methods
    • Opioid-Related Disorders/etiology
    • Analgesics, Opioid/administration & dosage


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