Kappa Opioids, Salvinorin A and Major Depressive Disorder

Abstract

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.

Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism

“…Thus our data do not distinguish between the respective roles mu opioid receptor and kappa opioid receptor in mediating ketamine’s antidepressant effects. Nonetheless, given the available data implicating mu opioid receptor-based mechanisms of antidepressant efficacy, inconsistent findings regarding kappa opioid receptor antagonists in depression (57, 58), and ketamine’s putative kappa agonist mechanism (21, 59), we favor the interpretation that ketamine produces its acute antidepressant response primarily through direct and/or indirect actions at the mu opioid receptors. Naltrexone when chronically administered alone in normal healthy controls as well as individuals with mood and substance disorders has been demonstrated to either act as an antidepressant or be moodneutral across several placebo-controlled trials (23, 33–38), suggesting that naltrexone is not simply acting as a depressionogenic agent in this case, but rather providing selective blockade of the antidepressant effects produced by ketamine.…”

Targeting multiple opioid receptors – improved analgesics with reduced side effects?

“…While κ receptor agonists frequently precipitate dysphoric mood changes in humans and depression‐like symptoms in experimental animals (Ranganathan et al , ), several κ receptor antagonists were found to exert anti‐depressant effects (Lutz and Kieffer, ) (Table ). A combined pharmacological profile of a μ receptor agonist and κ receptor antagonist could thus not only produce analgesia but also treat depressive symptoms, a frequent comorbidity in chronic pain patients (Taylor and Manzella, ). The compound best studied in this context is buprenorphine, which is a partial μ receptor agonist with a weak κ receptor antagonistic profile.…”

International Union of Basic and Clinical Pharmacology CIV: The Neurobiology of Treatment-resistant Depression: From Antidepressant Classifications to Novel Pharmacological Targets

“…It has been hypothesized that activation of KOR receptor by dynorphin leads to a reduction in dopamine release, thus producing anhedonia and depressive symptoms. Accordingly, KOR antagonists exert relevant antidepressant effects in animal models of depression (Taylor and Manzella, 2016).…”