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. Here, OPRK1 is linked to depressive disorder.