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

  • Gerta Cami-Kobeci
    ,
  • Norikazu Kiguchi
    ,
  • Huiping Ding
    ,
  • Devki D. Sukhtankar
    ,
  • Paul W. Czoty
    ,
  • Heather B. DeLoid
  • Wakayama Medical University
    ,
  • Wake Forest University
    ,
  • Florida Atlantic University
    ,
  • University of Bath
Research Output:
Contribution to journal
Article
 Peer-review

Open access

Abstract

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.

Publication Information

Output type

Research Output:
Contribution to journal
Article
 Peer-review

Original language

English

Pages from-to (Number of pages)

Pages e146-e156

Journal (Volume, Issue Number)

British Journal of Anaesthesia (Volume 122, Issue 6)

Publication milestones

  • Accepted/In press - 23/10/2018
  • Published - 01/03/2019

Publication status

Published - 01/03/2019

ISSN

0007-0912

Publication IDs

  • handle.net: 10547/624677
  • Scopus: 85062068635

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