BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates
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Authors
Kiguchi, NorikazuDing, Huiping
Cami-Kobeci, Gerta
Sukhtankar, Devki D.
Czoty, Paul W.
DeLoid, Heather B.
Hsu, Fang-Chi
Toll, Lawrence
Husbands, Stephen M.
Ko, Mei-Chuan
Affiliation
Wake Forest UniversityWakayama Medical University
University of Bath
Wake Forest Baptist Medical Center
Florida Atlantic University
W.G. Hefner Veterans Affairs Medical Center
Issue Date
2019-03-01Subjects
analgesicsrhesus macaque
opiate addiction
respiration
opioid
opioid-related disorders
Subject Categories::B200 Pharmacology, Toxicology and Pharmacy
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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.Citation
Kiguchi N, Ding H, Cami-Kobeci G, Sukhtankar DD, Czoty PW, DeLoid HB, Hsu FC, Toll L, Husbands SM, Ko MC (2019) 'BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates', British Journal of Anaesthesia, 122 (6), pp.e146-e156.Publisher
Elsevier LtdJournal
British Journal of AnaesthesiaPubMed ID
30916003Additional Links
https://www.bjanaesthesia.org.uk/article/S0007-0912(19)30048-0/fulltexthttps://www.sciencedirect.com/science/article/pii/S0007091219300480
Type
ArticleLanguage
enISSN
0007-0912ae974a485f413a2113503eed53cd6c53
10.1016/j.bja.2018.10.065
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