# An Experimental Study to Evaluate the Role of Buprenorphine, Morphine, and Naltrexone in Animal Models of Depression

## TL;DR

This study tests how buprenorphine, morphine, and naltrexone affect depression-like behaviors in stressed mice, finding that buprenorphine alone or with naltrexone shows strong antidepressant effects.

## Contribution

The study introduces buprenorphine-based regimens as novel candidates for treating depression by combining KOR antagonism with abuse liability reduction.

## Key findings

- Buprenorphine reversed depression-like behaviors in mice as effectively as fluoxetine.
- Combining buprenorphine with naltrexone preserved antidepressant effects while potentially reducing abuse risk.
- Morphine and naltrexone alone showed inconsistent or partial effects on depression-like symptoms.

## Abstract

Background: Opioids have a long-standing history of being used for the treatment of mood disorders, with recent attention directed towards kappa opioid receptors (KOR) for antidepressant drug development. Activation of KOR produces dysphoria and anhedonia, whereas antagonism confers antidepressant-like effects. Buprenorphine, a partial mu-opioid receptor (MOR) agonist and KOR antagonist, exhibits antidepressant properties but carries a risk of abuse liability. Naltrexone, a non-selective opioid antagonist, may mitigate this risk while preserving KOR antagonism. This study evaluated the antidepressant-like effects of buprenorphine, morphine, and naltrexone individually, as well as the combination of buprenorphine and morphine with naltrexone, in validated models of depression.

Experimental approach: Male mice were subjected to unpredictable chronic mild stress (UCMS) for four weeks. Following stress induction, drug treatments were administered for 14 days: buprenorphine (1 mg/kg), naltrexone (1 mg/kg), morphine (5 mg/kg), their combinations, or fluoxetine (10 mg/kg) as a reference. Behavioral assessments included the Sucrose Preference Test (SPT), Open Field Test (OFT), Forced Swim Test (FST), and Tail Suspension Test (TST).

Results: UCMS induced anhedonia and behavioral suppression, confirmed by reduced sucrose consumption, locomotor activity, and increased immobility. Buprenorphine significantly reversed these effects across all assays, with efficacy comparable to fluoxetine. The buprenorphine-naltrexone combination also produced significant antidepressant-like effects, though slightly less pronounced than buprenorphine alone. Morphine and naltrexone showed partial or inconsistent effects.

Conclusion: Buprenorphine demonstrated robust antidepressant-like activity in UCMS, likely mediated by KOR antagonism with contributions from MOR, delta-opioid, and nociceptin opioid peptide (NOP) receptors. Co-administration with naltrexone preserved efficacy while potentially reducing abuse liability. These findings highlight buprenorphine-based regimens as mechanistically novel candidates for further evaluation in treatment-resistant depression.