dynorphins and Depressive-Disorder--Major

The kappa opioid receptor (KOR) and its endogenous ligands dynorphins (DYN) have been implicated in the development or symptomatology of a variety of neuropsychiatric disorders. This review covers a brief history of the development of KOR agonists and antagonists, their effects in healthy volunteers, and the potential role of DYN/KOR dysfunction in schizophrenia and major depressive disorder from a translational perspective. The potential role of DYN/KOR dysfunction in schizophrenia is based on several lines of evidence. Selective KOR agonists induce affective states in healthy volunteers with similarities to the symptoms of schizophrenia. Studies have shown increased DYN in patients with schizophrenia, although the data have been mixed. Finally, meta-analytic data have shown that opioid antagonists are associated with reductions in the symptoms of schizophrenia. The potential role of DYN/KOR dysfunction in major depressive disorder is also based on a combination of preclinical and clinical data. Selective KOR agonists have shown pro-depressive effects in human volunteers, while selective KOR antagonists have shown robust efficacy in several preclinical models of antidepressant activity. Small studies have shown that nonselective KOR antagonists may have efficacy in treatment-resistant depression. Additionally, recent clinical data have shown that the KOR may be an effective target for treating anhedonia, a finding relevant to both schizophrenia and depression. Finally, recommendations are provided for translating preclinical models for schizophrenia and major depressive disorder into the clinic.

Topics: Depressive Disorder, Major; Dynorphins; Humans; Narcotic Antagonists; Receptors, Opioid, kappa; Schizophrenia

The kappa opioid receptor (KOR) is thought to regulate neural systems associated with anhedonia and aversion and mediate negative affective states that are associated with a number of psychiatric disorders, but especially major depressive disorder (MDD). Largely because KOR antagonists mitigate the effects of stress in preclinical studies, KOR antagonists have been recommended as novel drugs for treating MDD. The purpose of this review is to examine the role of KORs and its endogenous ligand dynorphins (DYNs) in the pathology and treatment of MDD derived from different types of clinical studies. Evidence pertaining to the role of KOR and MDD will be reviewed from (1) post mortem mRNA expression patterns in MDD, (2) the utility of KOR neuroimaging agents and serum biomarkers in MDD, and (3) evidence from the recent Fast Fail clinical trial that established KOR antagonism as a potential therapeutic strategy for the alleviation of anhedonia, a core feature of MDD. These findings are compared with a focused evaluation of stress-induced alterations in OPRK and PDYN mRNA expression. Finally, the current status of the effects of KOR antagonists on behavioral phenotypes of stress in preclinical studies related to MDD is summarized.

Topics: Depressive Disorder, Major; Dynorphins; Humans; Narcotic Antagonists; Receptors, Opioid, kappa

Topics: Animals; Behavior, Addictive; Benzamides; Depressive Disorder, Major; Dynorphins; Humans; Pyrrolidines; Receptors, Opioid, kappa; Stress, Psychological

Opioids are traditionally associated with pain, analgesia and drug abuse. It is now clear, however, that the opioids are central players in mood. The implications for mood disorders, particularly clinical depression, suggest a paradigm shift from the monoamine neurotransmitters to the opioids either alone or in interaction with monoamine neurons. We have a special interest in dynorphin, the last of the major endogenous opioids to be isolated and identified. Dynorphin is derived from the Greek word for power, dynamis, which hints at the expectation that the neuropeptide held for its discoverers. Yet, dynorphin and its opioid receptor subtype, kappa, has always taken a backseat to the endogenous b-endorphin and the exogenous morphine that both bind the mu opioid receptor subtype. That may be changing as the dynorphin/ kappa system has been shown to have different, often opposite, neurophysiological and behavioral influences. This includes major depressive disorder (MDD). Here, we have undertaken a review of dynorphin/ kappa neurobiology as related to behaviors, especially MDD. Highlights include the unique features of dynorphin and kappa receptors and the special relation of a plant-based agonist of the kappa receptor salvinorin A. In addition to acting as a kappa opioid agonist, we conclude that salvinorin A has a complex pharmacologic profile, with potential additional mechanisms of action. Its unique neurophysiological effects make Salvinorina A an ideal candidate for MDD treatment research.

Topics: Anhedonia; Animals; Brain; Depressive Disorder, Major; Diterpenes, Clerodane; Dynorphins; Humans; Receptors, Opioid, kappa

Major depression disorder is a severe and recurrent neuropsychological disorder characterized by lowered mood and social activity and cognitive impairment. Owing to unclear molecular mechanisms of depression, limited interventions are available in clinic. In this study we investigated the role of dynorphin/κ opioid receptor system in the development of depression. Mice were subjected to chronic social defeat stress for 14 days. Chronic social defeat stress induced significant social avoidance in mice characterized by decreased time duration in the interaction zone and increased time duration in the corner zone. Pre-administration of a κ opioid receptor antagonist norBNI (10 mg/kg, i.p.) could prevent the development of social avoidance induced by chronic social defeat stress. Social avoidance was not observed in κ opioid receptor knockout mice subjected to chronic social defeat stress. We further revealed that social defeat stress activated c-fos and ERK signaling in the amygdala without affecting the NAc, hippocampus and hypothalamus, and ERK activation was blocked by systemic injection of norBNI. Finally, the expression of dynorphin A, the endogenous ligand of κ opioid receptor, was significantly increased in the amygdala following social defeat stress; microinjection of norBNI into the amygdala prevented the development of depressive-like behaviors caused by social defeat stress. The present study demonstrates that upregulated dynorphin/κ opioid receptor system in the amygdala leads to the emergence of depression following chronic social defeat stress, and sheds light on κ opioid receptor antagonists as potential therapeutic agents for the prevention and treatment of depression following chronic stress.

Topics: Amygdala; Animals; Behavior, Animal; Depressive Disorder, Major; Dynorphins; Extracellular Signal-Regulated MAP Kinases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Naltrexone; Proto-Oncogene Proteins c-fos; Receptors, Opioid, kappa; Social Behavior; Social Defeat