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

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.

Figure 1

Chemical structures of buprenorphine and BU10119.

Figure 2

Effects of BU10119 in adult male CD1 mice in the warm‐water tail‐withdrawal assay. The time course of the experiments is indicated, and tail‐withdrawal latencies are expressed as %MPE. (A) Antinociceptive effects of buprenorphine (1 mg·kg⁻¹) and BU10119 (0.3, 1 and 3 mg·kg⁻¹). *P < 0.05 as compared between buprenorphine and all other groups. (B) Antinociceptive effects of the κ‐agonist U50,488 (10 mg·kg⁻¹) were blocked by BU10119 (1 and 3 mg·kg⁻¹) and by norBNI (1 mg·kg⁻¹). *P < 0.05 as compared to BU10119 (1 and 3 mg·kg⁻¹) and norBNI (1 mg·kg⁻¹), #P < 0.05 as compared between all groups and norBNI (1 mg·kg⁻¹). (C) Antinociceptive effects of buprenorphine and morphine at 60 min post‐administration were blocked by BU10119 (1 mg·kg⁻¹) and by the irreversible μ‐antagonist CCAM (3 mg·kg⁻¹). *P < 0.05 compared to buprenorphine; #P < 0.05 compared to morphine. All values are mean ± SEM, n = 5 per group, separate experimental groups in each figure.

Figure 3

Locomotor activity in the open field in adult male CD1 mice treated with BU10199 (0.3, 1 and 3 mg·kg⁻¹). All values are mean ± SEM, n = 5 per group. No statistically significant effects on locomotion were observed.

Figure 4

Conditioned place preference (CPP) to buprenorphine (BUP, 1 mg·kg⁻¹), BU10119 (1 mg·kg⁻¹) and morphine (10 mg·kg⁻¹). Two separate experiments were conducted. (A) BU10119 did not produce significant CPP. CPP to buprenorphine was not blocked in the presence of the irreversible μ antagonist CCAM (3 mg·kg⁻¹). (B) The activity of CCAM as a μ antagonist was confirmed by its ability to block morphine‐induced CPP. Data are presented as preference for drug‐paired side of CPP chamber, determined as the time spent in drug‐paired side (post‐conditioning) minus time spent in drug‐paired side pre‐conditioning (baseline). All data points are mean ± SEM. (A) *P < 0.05 compared to saline, n = 9 per treatment group. (B) *P < 0.05 compared to morphine, n = 8 per treatment group.

Figure 5

Effects of BU10119 (1 mg·kg⁻¹) in adult male CD1 mice in the forced swim test (A) and in the novelty‐induced hypophagia task (B). The SSRI fluoxetine (20 mg·kg⁻¹) was administered as a positive control. The effects of combination of buprenorphine with naltrexone (both at 1 mg·kg⁻¹, BUP/NTX) and the κ antagonist norBNI are also shown. (A) The total time spent swimming, climbing or immobile during the last 4 min of the forced swim session are shown. (B) The latency to drink milk in both the home and novel cage environments is shown. All values are the mean ± SEM (n = 10 per group, separate experimental groups in each figure). *P < 0.05 as compared to saline; #P < 0.05 for comparison between groups.

Figure 6

Effects of BU10119 (1 mg·kg⁻¹) in adult CD1 male mice in the elevated plus maze (EPM; A–C) and in the light‐dark box (LDB; D–F). The effects of combination of buprenorphine with naltrexone (both at 1 mg·kg⁻¹, BUP/NTX) are also shown. The benzodiazepine diazepam (2 mg·kg⁻¹) was used as a positive control. The time spent in the open arms (A), number of entries into the open arms (as a percentage of the total entries into open and closed arms) (B) and total ambulation (C) in the EPM are shown (n = 10 per group). The time spent in the light box (D), in the dark box (E) and total ambulation (F) in the LDB are shown (n = 18 per treatment group, n = 10 for BU10119). All values are the mean ± SEM. *P < 0.05 compared to saline.

Figure 7

Ability of BU10119 (1 mg·kg⁻¹), the combination of buprenorphine/naltrexone (both at 1 mg·kg⁻¹, BUP/NTX) and the κ antagonist norBNI to block stress‐induced effects. Drug treatments were administered 1 h prior to acute restraint stress (1 × 2 h, Day 1) and daily repeated restraint stress (3 × 2 h, Day 3) in adult male CD1 mice. (A) Stress‐induced analgesia was evident, in the warm‐water tail‐withdrawal assay, as increased %MPE. Test latencies were assessed immediately following the restraint session. *P < 0.05 compared to all groups within the same day. (B) Blood samples were taken at baseline and immediately following the last session of restraint to assess plasma corticosterone. All blood samples were taken during the light phase 11:00–13:00 h. *P < 0.05, compared to non‐stress saline post day 3; #P < 0.05, compared to baseline for the same treated group. All values are the mean ± SEM (n = 6 per group, separate experimental groups in A and B).