Combined administration of buprenorphine and naltrexone produces antidepressant-like effects in mice

Abstract

Opiates have been used historically for the treatment of depression. Renewed interest in the use of opiates as antidepressants has focused on the development of kappa opioid receptor (κ-receptor) antagonists. Buprenorphine acts as a partial µ-opioid receptor agonist and a κ-receptor antagonist. By combining buprenorphine with the opioid antagonist naltrexone, the activation of µ-opioid receptors will be reduced and the κ-antagonist properties enhanced. We have established that a combination dose of buprenorphine (1 mg/kg) with naltrexone (1 mg/kg) functions as a short-acting κ-antagonist in the mouse tail withdrawal test. Furthermore, this dose combination is neither rewarding nor aversive in the conditioned place preference paradigm, and is without significant locomotor effects. We have shown for the first time that systemic co-administration of buprenorphine (1 mg/kg) with naltrexone (1 mg/kg) in CD-1 mice produced an antidepressant-like response in behaviours in both the forced swim test and novelty induced hypophagia task. Behaviours in the elevated plus maze and light dark box were not significantly altered by treatment with buprenorphine alone, or in combination with naltrexone. We propose that the combination of buprenorphine with naltrexone represents a novel, and potentially a readily translatable approach, to the treatment of depression.

Keywords: Depression; anxiety; kappa antagonist; kappa opioid receptor; mu agonist.

Figure 1

Antinociceptive effects of buprenorphine (Bup, 1mg/kg) and U50,488 (U50, 10 mg/kg) are blocked by naltrexone (NTX) in the mouse tail withdrawal assay. The time course of the experiments is shown (A,C, E). Bar charts highlight the antagonist effects of naltrexone (NTX) at 60 min post-administration of agonist (B, D). (A,B) Naltrexone (NTX) dose-dependently blocked buprenorphine-induced antinociception (**p< 0.01; ***p< 0.001 Bup compared to saline control; ^$$p< 0.01; ^$$$p< 0.001 Bup alone compared to combination Bup + NTX 1 and 3 mg/kg). (C,D) Naltrexone (NTX) dose-dependently blocked U50,488-induced antinociception (*p< 0.05; **p< 0.01; ***p< 0.001 U50 compared to saline control; ^$$p< 0.01; ^$$$p< 0.001 U50 alone compared to combination U50 + NTX 1 and 3 mg/kg). (E) Duration of κ-antagonist effects of naltrexone alone or naltrexone/buprenorphine combination. Significant blockade of U50,488 induced antinociception is evident at 1 h post-administration and reversed by 24 h. At 8h post-administration, the combination of buprenorphine/naltrexone, produced a significant potentiation of U50-488-induced antinociception (^{^^^}p<0.001 compared to all other treatment groups; ### p<0.001 for all treatment groups compared to NTX/Bup/saline controls; && p<0.01 compared to NTX/Bup/saline controls and compared to NTX/Saline/U50 group. (F) The irreversible μ-antagonist CCAM (3 mg/kg) administered 24 h before testing blocked the NTX/Bup mediated potentiation of U50,488-induced antinociception at 8h post-administration (*p< 0.05 compared to U50 alone). All values are mean ± SEM, n= 5 per group.

Figure 2

Locomotor activity in the open field in mice treated with buprenorphine (Bup, 1mg/kg) alone and in combination with naltrexone (NTX) (0.3, 1 and 3 mg/kg). All values are mean ± SEM, n= 5 per group.

Figure 3

Conditioned place preference to buprenorphine (Bup, 1 mg/kg) in mice, in the presence and absence of naltrexone (NTX) (1 and 3 mg/kg). In a 900 s test, animals in all treatment groups did not show preference for either chamber during habituation (pre-conditioning). After 6 days of conditioning, buprenorphine significantly increased the time spent in the drug-paired chamber. Values are mean ± SEM, n = 8 per group. *p=0.05 vs pre-condition group.

Figure 4

Effects of buprenorphine (1mg/kg) and naltrexone (1mg/kg), alone or in combination, in the mouse forced swim test. The SSRI fluoxetine (20 mg/kg) was administered as a positive control. (A) All compounds under test produced antidepressant-like effects in the forced swim test. (B) The irreversible μ-antagonist CCAM (3mg/kg), administered 24h before buprenorphine, did not block the antidepressant-like effects of buprenorphine in the forced swim test. Data are expressed as mean ± SEM (n=10 per group) of time spent swimming, climbing and immobile during the last 4 min of a 6 min swim test. * p< 0.05, ** p< 0.01, ***p< 0.001 compared to saline.

Figure 5

Effects of buprenorphine (1mg/kg) and naltrexone (1mg/kg), alone or in combination, in the mouse novelty-induced hypophagia task. The latency to drink milk in both the home and novel cage environments is shown. (A) The SSRI fluoxetine (20 mg/kg) was administered as a positive control and the selective κ-antagonist norBNI (10 mg/kg) shown for comparison (n=10 per group). (B) The irreversible μ-antagonist CCAM (3 mg/kg) blocked the effects of buprenorphine (1 mg/kg) on latency to drink in the home cage, but not the novel cage (n=9 per group). Data are mean ± SEM. *p< 0.05, **p< 0.01 and ***p< 0.001 compared to saline. #p< 0.05 and ###p< 0.001 for novel cage comparison to home cage. ^{^^^}p< 0.001 compared to buprenorphine alone.

Figure 6

Effects of buprenorphine (1mg/kg) and naltrexone (1mg/kg), alone or in combination, in the mouse elevated plus maze (A,B,C) and light-dark box (D,E,F). The benzodiazepine diazepam (2 mg/kg) was included as a positive control. The time spent in the open arms (A), number of entries into the open arms (B) and total ambulation (C) in the elevated plus maze 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 light dark box are shown (n=18 per group). All values are the mean ± SEM. *p< 0.05 compared to saline.