13631
title and abstract
The atypical antidepressant mianserin exhibits agonist activity at kappa-opioid receptors.
BACKGROUND AND PURPOSE: Antidepressants 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 APPROACH: Effects 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 [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: Mianserin displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, mianserin selectively activated kappa-opioid receptors. The agonist activity was antagonized by the selective kappa-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed kappa-opioid agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing kappa-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full kappa-opioid agonists (-)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full kappa-opioid receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, mianserin directly activates kappa-opioid receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants.