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Research ArticleNEUROPHARMACOLOGY

Direct Agonist Activity of Tricyclic Antidepressants at Distinct Opioid Receptor Subtypes

Pierluigi Onali, Simona Dedoni and Maria C. Olianas
Journal of Pharmacology and Experimental Therapeutics January 2010, 332 (1) 255-265; DOI: https://doi.org/10.1124/jpet.109.159939
Pierluigi Onali
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Simona Dedoni
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Maria C. Olianas
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Abstract

Tricyclic antidepressants (TCAs) have been reported to interact with the opioid system, but their pharmacological activity at opioid receptors has not yet been elucidated. In the present study, we investigated the actions of amoxapine, amitriptyline, nortriptyline, desipramine, and imipramine at distinct cloned and native opioid receptors. In Chinese hamster ovary (CHO) cells expressing δ-opioid receptors (CHO/DOR), TCAs displaced [3H]naltrindole binding and stimulated guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding at micromolar concentrations with amoxapine displaying the highest potency and efficacy. Amoxapine and amitriptyline inhibited cyclic AMP formation and induced the phosphorylation of signaling molecules along the extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol-3 kinase pathways. Amoxapine also activated δ-opioid receptors in rat dorsal striatum and nucleus accumbens and human frontal cortex. In CHO cells expressing κ-opioid receptors (CHO/KOR), TCAs, but not amoxapine, exhibited higher receptor affinity and more potent stimulation of [35S]GTPγS binding than in CHO/DOR and effectively inhibited cyclic AMP accumulation. Amitriptyline regulated ERK1/2 phosphorylation and activity in CHO/KOR and C6 glioma cells endogenously expressing κ-opioid receptors, and this effect was attenuated by the κ-opioid antagonist nor-binaltorphimine. In rat nucleus accumbens, amitriptyline slightly inhibited adenylyl cyclase activity and counteracted the inhibitory effect of the full κ agonist trans-(−)-3,4dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50,488). At the cloned μ-opioid receptor, TCAs showed low affinity and no significant agonist activity. These results show that TCAs differentially regulate opioid receptors with a preferential agonist activity on either δ or κ subtypes and suggest that this property may contribute to their therapeutic and/or side effects.

Footnotes

  • This work was supported by a grant from the Ministry of Education, University, and Research of Italy.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.109.159939

  • ABBREVIATIONS:

    TCA
    tricyclic antidepressant
    CHO
    Chinese hamster ovary
    [35S]GTPγS
    guanosine 5′-O-(3-[35S]thio)triphosphate
    NTI
    naltrindole
    FSK
    forskolin
    (−)-U50,488
    trans-(−)-3,4dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide
    nor-BNI
    nor-binaltorphimine dihydrochloride
    CTAP
    d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2
    DPDPE
    (2-d-penicillamine, 5-d-penicillamine)-enkephalin
    DAMGO
    d-Ala2-N-methyl-Phe-Gly-ol5)-enkephalin
    pGSK
    phospho-Ser9-glycogen synthase kinase-3β
    pS6rp
    phospho-Ser235/236-S6 ribosomal protein
    ERK
    extracellular signal-regulated kinase
    pERK1/2
    phosphorylation of extracellular signal-regulated kinase 1/2
    GSK
    glycogen synthase
    pAkt
    phospho-Thr308-protein kinase B/Akt
    CHO/DOR
    /KOR, /MOR, CHO cells expressing the human δ-, κ-, and μ-opioid receptor, respectively
    PBS
    phosphate-buffered saline
    BSA
    bovine serum albumin
    ECL
    enhanced chemiluminescence
    ANOVA
    analysis of variance.

    • Received August 4, 2009.
    • Accepted October 13, 2009.
  • © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 332 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 332, Issue 1
1 Jan 2010
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Research ArticleNEUROPHARMACOLOGY

Direct Agonist Activity of Tricyclic Antidepressants at Distinct Opioid Receptor Subtypes

Pierluigi Onali, Simona Dedoni and Maria C. Olianas
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 255-265; DOI: https://doi.org/10.1124/jpet.109.159939

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Research ArticleNEUROPHARMACOLOGY

Direct Agonist Activity of Tricyclic Antidepressants at Distinct Opioid Receptor Subtypes

Pierluigi Onali, Simona Dedoni and Maria C. Olianas
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 255-265; DOI: https://doi.org/10.1124/jpet.109.159939
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