The atypical antidepressant mianserin exhibits agonist activity at κ-opioid receptors.
OBJECTIVE
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.


METHODS
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]GTPγS binding and MAPK phosphorylation.


RESULTS
Mianserin displayed 12- and 18-fold higher affinity for κ- than µ- and δ-opioid receptors respectively. In [(35)S]GTPγS assays, mianserin selectively activated κ-opioid receptors. The agonist activity was antagonized by the selective κ-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed κ-opioid agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing κ-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPγS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full κ-opioid agonists (-)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full κ-opioid receptor agonists in [(35)S]GTPγS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A.


CONCLUSIONS
In different cell systems, mianserin directly activates κ-opioid receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants.
Section of Biochemical Pharmacology, Department of Neuroscience, University of Cagliari, Cagliari, Italy.
Maria C
MC
Olianas
Simona
S
Dedoni
Pierluigi
P
Onali
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D050882:CREB-Binding Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D008297:Male; D008803:Mianserin / Q000494:pharmacology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism
D018687:Antidepressive Agents, Second-Generation; D017473:Receptors, Opioid, kappa; D011994:Recombinant Proteins; D008803:Mianserin; D050882:CREB-Binding Protein; D020928:Mitogen-Activated Protein Kinases