The involvement of the KOR in stress, as well as in consequences of chronic stress such as depression, anxiety, anhedonia, and increased drug-seeking behavior, has been elucidated.[11] KOR agonists are notably dysphoric and aversive at sufficient doses.[17] The KOR antagonists buprenorphine, as ALKS-5461 (a combination formulation with samidorphan), and CERC-501 (LY-2456302) are currently in clinical development for the treatment of major depressive disorder and substance use disorders.[18] JDTic and PF-4455242 were also under investigation but development was halted in both cases due to toxicity concerns.[18] (For more information on the KOR in drug addiction, see below.)
The depressive-like behaviors following prolonged morphine abstinence appear to be mediated by upregulation of the KOR/dynorphin system in the nucleus accumbens, as the local application of a KOR antagonist prevented the behaviors.[19] As such, KOR antagonists might be useful for the treatment of depressive symptoms associated with opioid withdrawal.[19]
In a small clinical study, pentazocine, a KOR agonist, was found to rapidly and substantially reduce symptoms of mania in individuals with bipolar disorder that were in the manic phase of the condition.[20] It was postulated that the efficacy observed was due to KOR activation-mediated amelioration of hyperdopaminergia in the reward pathways.