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

Norikazu Kiguchi, H Ding, Gerta Cami-Kobeci, D. D. Sukhtankar, P. W. Czoty, H. B. DeLoid, F. -C. Hsu, L. Toll, Stephen Husbands, M. C. Ko

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.
LanguageEnglish
JournalBritish Journal of Anaesthesia
Early online date1 Mar 2019
DOIs
StatusE-pub ahead of print - 1 Mar 2019

Cite this

BU10038 as a safe opioid analgesic with fewer side effects after systemic and intrathecal administration in primates. / Kiguchi, Norikazu; Ding, H; Cami-Kobeci, Gerta; Sukhtankar, D. D.; Czoty, P. W.; DeLoid, H. B.; Hsu, F. -C.; Toll, L.; Husbands, Stephen; Ko, M. C.

In: British Journal of Anaesthesia, 01.03.2019.

Research output: Contribution to journalArticle

Kiguchi, Norikazu ; Ding, H ; Cami-Kobeci, Gerta ; Sukhtankar, D. D. ; Czoty, P. W. ; DeLoid, H. B. ; Hsu, F. -C. ; Toll, L. ; Husbands, Stephen ; Ko, M. C. / BU10038 as a safe opioid analgesic with fewer side effects after systemic and intrathecal administration in primates. In: British Journal of Anaesthesia. 2019.
@article{e04eafbadac14df48e03e96c972998d2,
title = "BU10038 as a safe opioid analgesic with fewer side effects after systemic and intrathecal administration in primates",
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.",
author = "Norikazu Kiguchi and H Ding and Gerta Cami-Kobeci and Sukhtankar, {D. D.} and Czoty, {P. W.} and DeLoid, {H. B.} and Hsu, {F. -C.} and L. Toll and Stephen Husbands and Ko, {M. C.}",
year = "2019",
month = "3",
day = "1",
doi = "10.1016/j.bja.2018.10.065",
language = "English",
journal = "British Journal of Anaesthesia",
issn = "0007-0912",
publisher = "Oxford University Press",

}

TY - JOUR

T1 - BU10038 as a safe opioid analgesic with fewer side effects after systemic and intrathecal administration in primates

AU - Kiguchi, Norikazu

AU - Ding, H

AU - Cami-Kobeci, Gerta

AU - Sukhtankar, D. D.

AU - Czoty, P. W.

AU - DeLoid, H. B.

AU - Hsu, F. -C.

AU - Toll, L.

AU - Husbands, Stephen

AU - Ko, M. C.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - 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.

AB - 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.

U2 - 10.1016/j.bja.2018.10.065

DO - 10.1016/j.bja.2018.10.065

M3 - Article

JO - British Journal of Anaesthesia

T2 - British Journal of Anaesthesia

JF - British Journal of Anaesthesia

SN - 0007-0912

ER -