Differential activity of antidepressants at human opioid receptor subtypes

OLIANAS, MARIA CONCETTA;DEDONI, SIMONA;GARAU L;ONALI, PIER LUIGI

2008-01-01

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Abstract

Antidepressants are known to possess analgesic properties and have been shown to interact with the opioid system by either enhancing endogenous opioid levels or displacing opioid ligands from binding sites. However, little is known on the activity of these drugs at the distinct opioid receptor subtypes. In the present study we investigated the interaction of the tricyclic antidepressants amoxapine, nortriptyline, amitriptyline, desipramine and imipramine and the SSRI antidepressant fluoxetine with each of the cloned human opioid receptors individually expressed in Chinese hamster ovary cells. We found that amoxapine behaved as a full δ receptor agonist in stimulating [35S]GTPγS binding with a potency in the low micromolar range. Moreover in cells expressing the δ receptor, amoxapine induced a rapid phosphorylation of Thr308-Akt-1, Ser9-glycogen synthase kinase 3β and ERK1/2. Amoxapine was a much weaker agonist at the κ receptor and had no activity at µ and NOP receptors. Instead, the other tricyclic antidepressants were more potent and effective agonists at κ than δ receptors, and were inactive at µ and NOP receptors. On the other hand, fluoxetine displayed agonist activity at κ but not at µ and δ receptors. Moreover, it antagonized the action of the δ agonist DPDPE. These data indicate that antidepressants can act as agonists at opioid receptors and display differential activity toward the distinct subtypes. These properties may be relevant for their analgesic action and clinical profile.