A role for the mu opioid receptor in the antidepressant effects of buprenorphine

Abstract

Buprenorphine (BPN), a mixed opioid drug with high affinity for mu (MOR) and kappa (KOR) opioid receptors, has been shown to produce behavioral responses in rodents that are similar to those of antidepressant and anxiolytic drugs. Although recent studies have identified KORs as a primary mediator of BPN’s effects in rodent models of depressive-like behavior, the role of MORs in BPN’s behavioral effects has not been as well explored. The current studies investigated the role of MORs in mediating conditioned approach behavior in the novelty-induced hypophagia (NIH) test, a behavioral measure previously shown to be sensitive to chronic treatment with antidepressant drugs. The effects of BPN were evaluated in the NIH test 24 h post-administration in mice with genetic deletion of the MOR (Oprm1−/−) or KOR (Oprk1−/−), or after pharmacological blockade with the non-selective opioid receptor antagonist naltrexone and selective MOR antagonist cyprodime. We found that behavioral responses to BPN in the NIH test were blocked in Oprm1−/− mice, but not in Oprk1−/− mice. Both cyprodime and naltrexone significantly reduced approach latency at doses experimentally proven to antagonize the MOR. In contrast the selective MOR agonist morphine and the selective KOR antagonist nor-BNI were both ineffective. Moreover, antinociceptive studies revealed persistence of the MOR antagonist properties of BPN at 24 h post-administration, the period of behavioral reactivity. These data support modulation of MOR activity as a key component of BPN’s antidepressant-like effects in the NIH paradigm.

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

“…In the Oprm1 A112G mouse model, BPN produced a robust effect in the AA mice but failed to diminish the anxiogenic effects of the novel environment in AG and GG mice, suggesting that altered genetic signaling at MORs mediated these behavioral differences. In agreement with this characterization, approach behavior in the NIH test was blocked by the selective MOR antagonist cyprodime and in male Oprm1 −/− mice (Robinson et al, 2016). Conversely, we showed that the prototypical benzodiazepine CDP was highly efficacious across all genotypes, demonstrating the specific ability of Oprm1 A112G SNP to attenuate the efficacy of MOR compounds.…”

“…BPN (0.25 and 0.5 mg/kg) reduced the latency to consume palatable food in the NIH test 24 h post treatment in WT female C57BL/6J mice. It is proposed that blockade of MOR mediates this anxiolytic action, as MOR agonism is prevented by this dose of BPN 24 h post treatment (Robinson et al, 2016). In the Oprm1 A112G mouse model, BPN produced a robust effect in the AA mice but failed to diminish the anxiogenic effects of the novel environment in AG and GG mice, suggesting that altered genetic signaling at MORs mediated these behavioral differences.…”

The importance of buprenorphine research in the opioid crisis

“…The buprenorphine antidepressant activity in the forced swim test in mice is absent in OPRK1 (the gene encoding KOR) gene null mutants [53]. However, in the novelty-induced hypophagia test in mice, the antidepressant effects of buprenorphine were absent in OPRM1 null mutants but retained in OPRK1 null mutants [56]. Thus, the buprenorphine MOR and KOR activities may both be relevant to its effects on rodent models of anxiety and depression.…”

Targeting opioid receptor signaling in depression: do we need selective κ opioid receptor antagonists?

“…That this activity was mediated through blockade of MOP receptors was confirmed by use of a selective MOP receptor antagonist, cyprodime. These authors suggest that antagonism of MOP receptors by buprenorphine could block stress-induced activation of MOP receptors in the VTA which has been shown to reduce dopaminergic transmission in the nucleus accumbens [63]. It would therefore appear that both KOP receptor antagonism and MOP receptor antagonism may be important for buprenorphine's ability to regulate emotional state.…”

“…Initially it was believed that buprenorphine's efficacy in treating depressed patients was derived from its partial MOP agonist actions but this has been challenged in recent years with evidence suggesting these behavioural effects of buprenorphine can be attributed to its KOP receptor antagonism [58,69]. Intriguingly, the most recent data indicate that MOP receptors do play a role in buprenorphine's behavioural response where there is a motivational component [63,71] but perhaps not in the way initially envisaged. In the novelty-induced hypophagia task in C57BL/6J mice buprenorphine, when used at a time point when it was acting as an MOP receptor antagonist, reduced the latency to approach the food in the novel cage but not in MOP receptor knockout mice.…”