Antidepressant-like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors

Abstract

Previous studies have identified potential antidepressant effects of buprenorphine (BPN), a drug with high affinity for mu opioid receptor (MORs) and kappa opioid receptors (KORs) and some affinity at delta opioid receptor (DOR) and opioid receptor-like 1 (ORL-1) receptors. Therefore, these studies examined which opioid receptors were involved in BPN's effects on animal behavior tests sensitive to antidepressant drugs. The acute effects of BPN were tested in the forced swim test (FST) using mice with genetic deletion of individual opioid receptors or after pharmacological blockade of receptors. For evaluating the effects of BPN on chronic stress, separate groups of mice were exposed to unpredictable chronic mild stress (UCMS) for 3 weeks and treated with BPN for at least 7 days before behavioral assessment and subsequent measurement of Oprk1, Oprm1, and Pdyn mRNA expression in multiple brain regions. BPN did not reduce immobility in mice with KOR deletion or after pretreatment with norbinaltorphimine, even though desipramine remained effective. In contrast, BPN reduced immobility in MOR and DOR knockout mice and in mice pretreated with the ORL-1 antagonist JTC-801. UCMS reduced sucrose preference, decreased time in the light side of the light/dark box, increased immobility in the FST and induced regionspecific alterations in Oprk1, Oprm1, and PDYN mRNA expression in the frontal cortex and striatum. All of these changes were normalized following BPN treatment. The KOR was identified as a key player mediating the effects of BPN in tests sensitive to antidepressant drugs in mice. These studies support further development of BPN as a novel antidepressant.

Genetic variation in the behavioral effects of buprenorphine in female mice derived from a murine model of the OPRM1 A118G polymorphism

“…In addition to the treatment of opioid addiction and chronic pain, compelling clinical (Karp et al, 2014; Yovell et al, 2016) and preclinical evidence (Falcon et al, 2016) have recently highlighted the potential antidepressant effects of BPN. As such, BPN is likely to be repurposed for the treatment of major depressive disorder (MDD) in the near future.…”

What Is New about New Antidepressants?

“…Despite emerging data on the potential role of intracellular signals, gene expression, and network connectivity, many of these targets are still neurotransmitters and receptors. A few examples of such directions in antidepressant development are summarized in Table 2 [8, 23, 63, 64]. …”

Buprenorphine‐naloxone treatment responses differ between young adults with heroin and prescription opioid use disorders

“…The finding that the HU did not improve at all on depressive symptoms as expected with abstinence and the potential antidepressant-like effect of buprenorphine treatment 19 is remarkable. Studies that have evaluated depression with treatment response in HU have mixed results showing either worse 36 or better outcomes 33 .…”

“…Thus heroin and prescription opioids may have induced depressive symptoms differently by interacting in different ways with kappa opioid receptors (KOR) that mediates dysphoria, and/or with the delta opioid receptors (DOR) that is considered to decrease levels of anxiety and reduce depressive-like behaviors 38 . Likewise, the antidepressant-like effect of buprenorphine that is mediated by its antagonist effect at KOR 19 may have acted differently based on different profile changes effects of heroin vs prescription opiates on the different opioid receptors.…”

“…In addition, since we had excluded patients with major depressive disorders and those receiving or needing pharmacotherapy for any depressive disorder, we expected that any depressive symptoms at baseline would improve equally for both groups. This improvement in depressive symptoms was expected as they reduced their opioid use, became abstinent, regained psychosocial functioning, and benefit from any potential anti-depressant effects of buprenorphine 19 .…”