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.
T10 T11 T12 T13 T14 T15 T16 T17 T18 T19 T1 T20 T21 T22 T23 T24 T25 T26 T27 T28 T29 T2 T30 T31 T32 T33 T34 T35 T36 T37 T38 T39 T3 T40 T41 T42 T43 T4 T5 T6 T7 T8 T9
CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-N GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-N GENE-N GENE-N GENE-Y GENE-Y GENE-N GENE-N GENE-N GENE-N CHEMICAL GENE-N GENE-Y GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
[(35)S]GTPgammaS tricyclic dynorphin A mianserin mianserin mianserin [(35)S]GTPgammaS Mianserin [(35)S]GTPgammaS mianserin Mianserin nor-binaltorphimine nor-BNI mianserin mirtazapine mianserin kappa-opioid ERK1/2 kappa-opioid receptors kappa-opioid dynorphin A mirtazapine kappa-opioid receptor p38 MAPK ERK1/2 dynorphin A kappa-opioid receptors opioid receptors opioid receptors human opioid receptors MAPK nor-BNI kappa- than micro- and delta-opioid receptors kappa-opioid receptors kappa-opioid kappa-opioid receptors mianserin [35S]GTPgammaS nor-BNI (-)-U50,488 dynorphin A mianserin