The atypical antidepressant mianserin exhibits agonist activity at κ‐opioid receptors

Abstract

BACKGROUND AND PURPOSEAntidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACHEffects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [ KEY RESULTSMianserin displayed 12-and 18-fold higher affinity for k-than m-and d-opioid receptors respectively. In [ 35 S]GTPgS assays, mianserin selectively activated k-opioid receptors. The agonist activity was antagonized by the selective k-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed k-opioid agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing k-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full k-opioid agonists (-)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full k-opioid receptor agonists in [ CONCLUSIONS AND IMPLICATIONSIn different cell systems, mianserin directly activates k-opioid receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants.

LPA1 Mediates Antidepressant-Induced ERK1/2 Signaling and Protection from Oxidative Stress in Glial Cells

“…In agreement with our previous studies (Olianas et al, 2012), in C6 glioma cells and primary astrocytes ERK1/2 stimulation elicited by mianserin and other antidepressants, including amitriptyline, imipramine, desipramine, and mirtazapine, was suppressed by cell treatment with PTX, implying the involvement of the G i/o family of G proteins. This finding is also consistent with the observation that in different cell types LPA 1 induces ERK1/2 activity in a PTX-sensitive manner (Ishii et al, 2004) and further supports the participation of G i/o -coupled LPA 1 in the antidepressant actions in glial cells.…”

“…We have previously reported that in rat C6 glioma cells, amitriptyline and mianserin stimulated ERK1/2 phosphorylation by activating endogenous k-opioid receptors (Onali et al, 2010;Olianas et al, 2012). To examine whether the incomplete blockade observed with AM966 and Ki16425 was due to the concomitant stimulation of k-opioid receptors, cells were cotreated with the k-opioid receptor antagonist NBFI.…”

“…A major issue in understanding how antidepressants directly affect glial cell activity is the identification of the mechanisms by which these drugs can trigger intracellular signaling. Previous studies have reported that in glial cells distinct classes of antidepressants alter the subcellular localization of heterotrimeric G proteins (Donati and Rasenick, 2005), change the expression of b-arrestin 2 (Golan et al, 2010), and activate different receptor systems, including FGF-R (Hisaoka et al, 2011), 5HT 2B receptors (Li et al, 2008), and k-opioid receptors (Onali et al, 2010;Olianas et al, 2012). These studies suggest that antidepressants, besides inhibiting monoamine transporters in nerve terminals, possess the ability to affect different signaling molecules in glial cells.…”

LPA1 is a key mediator of intracellular signalling and neuroprotection triggered by tetracyclic antidepressants in hippocampal neurons

“…; Olianas et al . ). Pre‐treatment of HT22 cells with the κ‐opioid receptor antagonist norbinaltorphimine (100 nM) failed to block the stimulation of ERK1/2 phosphorylation elicited by mianserin (5 μM).…”

Kappa Opioid System Involvement in Mood and Anxiety Disorders

“…Other labs have been puzzled by the generalization that κ agonists, including SalvA, invariably induce depression and anxiety [15,31,63] Olianas and colleagues [64] pointed out that some medications used for treating mood disorders and anxiety are κ agonists. This includes both tricyclic and atypical antidepressants.…”