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

Background and Purpose The 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 (0.3-3mgkg(-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 (1x2h) or repeated restraint stress (3x daily 2h) to determine the ability of BU10119 to block stress-induced analgesia. Key Results BU10119 alone was without any antinociceptive activity. BU10119 (1mgkg(-1)) was able to block U50,488, buprenorphine and morphine-induced antinociception. The antagonist effects of BU10119 in the tail-withdrawal assay reversed between 24 and 48h. BU10119 was without significant locomotor or rewarding effects. BU10119 (1mgkg(-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 (1mgkg(-1)). Parallel stress-induced increases in plasma corticosterone were not affected. Conclusions and Implications BU10119 is a mixed / receptor antagonist with relatively short-duration antagonist activity. Based on these preclinical data, BU10119 has therapeutic potential for the treatment of depression and other stress-induced conditions.