Antidepressant-like effects of BU10119, a novel buprenorphine analogue with mixed κ/μ receptor antagonist properties, in mice

Abdulrahman Mohammed I Almatroudi, Mehrnoosh Ostovar, Christopher Bailey, Stephen Husbands, Sarah Bailey

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background and Purpose: The κ receptor antagonists have potential for treating neuropsychiatric disorders. We have investigated the in vivo pharmacology of a novel buprenorphine analogue, BU10119, for the first time. Experimental Approach: To determine the opioid pharmacology of BU10119 (0.3–3 mg·kg −1, i.p.) in vivo, the warm-water tail-withdrawal assay was applied in adult male CD1 mice. A range of behavioural paradigms was used to investigate the locomotor effects, rewarding properties and antidepressant or anxiolytic potential of BU10119. Additional groups of mice were exposed to a single (1 × 2 h) or repeated restraint stress (3× daily 2 h) to determine the ability of BU10119 to block stress-induced analgesia. Key Results: BU10119 alone was without any antinociceptive activity. BU10119 (1 mg·kg −1) was able to block U50,488, buprenorphine and morphine-induced antinociception. The κ antagonist effects of BU10119 in the tail-withdrawal assay reversed between 24 and 48 h. BU10119 was without significant locomotor or rewarding effects. BU10119 (1 mg·kg −1) significantly reduced the latency to feed in the novelty-induced hypophagia task and reduced immobility time in the forced swim test, compared to saline-treated animals. There were no significant effects of BU10119 in either the elevated plus maze or the light–dark box. Both acute and repeated restraint stress-induced analgesia were blocked by pretreatment with BU10119 (1 mg·kg −1). Parallel stress-induced increases in plasma corticosterone were not affected. Conclusions and Implications: BU10119 is a mixed κ/μ receptor antagonist with relatively short-duration κ antagonist activity. Based on these preclinical data, BU10119 has therapeutic potential for the treatment of depression and other stress-induced conditions. Linked Articles: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.

LanguageEnglish
Pages2869-2880
Number of pages12
JournalBritish Journal of Pharmacology
Volume175
Issue number14
Early online date6 Nov 2017
DOIs
StatusPublished - 1 Jul 2018

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Buprenorphine
kappa Opioid Receptor
Narcotic Antagonists
mu Opioid Receptor
Analgesia
Antidepressive Agents
Tail
Pharmacology
Anti-Anxiety Agents
Corticosterone
Morphine
Opioid Analgesics
Light
Water
Therapeutics

ASJC Scopus subject areas

  • Pharmacology

Cite this

Antidepressant-like effects of BU10119, a novel buprenorphine analogue with mixed κ/μ receptor antagonist properties, in mice. / Almatroudi, Abdulrahman Mohammed I; Ostovar, Mehrnoosh; Bailey, Christopher; Husbands, Stephen; Bailey, Sarah.

In: British Journal of Pharmacology, Vol. 175, No. 14, 01.07.2018, p. 2869-2880.

Research output: Contribution to journalArticle

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abstract = "Background and Purpose: The κ receptor antagonists have potential for treating neuropsychiatric disorders. We have investigated the in vivo pharmacology of a novel buprenorphine analogue, BU10119, for the first time. Experimental Approach: To determine the opioid pharmacology of BU10119 (0.3–3 mg·kg −1, i.p.) in vivo, the warm-water tail-withdrawal assay was applied in adult male CD1 mice. A range of behavioural paradigms was used to investigate the locomotor effects, rewarding properties and antidepressant or anxiolytic potential of BU10119. Additional groups of mice were exposed to a single (1 × 2 h) or repeated restraint stress (3× daily 2 h) to determine the ability of BU10119 to block stress-induced analgesia. Key Results: BU10119 alone was without any antinociceptive activity. BU10119 (1 mg·kg −1) was able to block U50,488, buprenorphine and morphine-induced antinociception. The κ antagonist effects of BU10119 in the tail-withdrawal assay reversed between 24 and 48 h. BU10119 was without significant locomotor or rewarding effects. BU10119 (1 mg·kg −1) significantly reduced the latency to feed in the novelty-induced hypophagia task and reduced immobility time in the forced swim test, compared to saline-treated animals. There were no significant effects of BU10119 in either the elevated plus maze or the light–dark box. Both acute and repeated restraint stress-induced analgesia were blocked by pretreatment with BU10119 (1 mg·kg −1). Parallel stress-induced increases in plasma corticosterone were not affected. Conclusions and Implications: BU10119 is a mixed κ/μ receptor antagonist with relatively short-duration κ antagonist activity. Based on these preclinical data, BU10119 has therapeutic potential for the treatment of depression and other stress-induced conditions. Linked Articles: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.",
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AU - Bailey, Christopher

AU - Husbands, Stephen

AU - Bailey, Sarah

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