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μ-Opioid receptor and α2-adrenoceptor agonist stimulation of [35S]GTPγS binding to G-proteins in postmortem brains of opioid addicts

Molecular Psychiatry volume 5, pages 308–315 (2000)Cite this article

Abstract

Repeated opioid administration has been associated in human brain with unaltered density of μ-opioid receptors (agonist radioligand binding sites and immunodetected receptor protein). These receptors are coupled to Gi/Go-proteins, which are increased in brain of heroin addicts. To assess the activity of G-proteins and their coupling to receptors after chronic opioid abuse, [35S]GTPγS binding was quantified in postmortem prefrontal cortices of 15 opioid-dependent subjects and 15 matched controls. The stimulation of [35S]GTPγS binding by the μ-opioid receptor agonist DAMGO or the α2-adrenoceptor agonist UK14304 was used as a functional measure of the status of the receptor-G-protein coupling. [35S]GTPγS binding basal values were similar in opioid addicts (819 ± 83 fmol mg−1 of protein) and controls (918 ± 106 fmol mg−1 of protein). In opioid addicts, [35S]GTPγS binding stimulation by DAMGO showed a maximal effect (62 ± 8%) and a potency (EC50 = 1.09 ± 0.26 μM) that did not differ from the maximal effect (60 ± 12%) and potency (EC50 = 2.01 ± 0.58 μM) in controls. In opioid addicts, [35S]GTPγS binding stimulation by UK14304 was not different in maximal effect (28 ± 3%) from controls (32 ± 8%), but the potency of the agonist was decreased (EC50 = 4.36 ± 1.81 μM) when compared with controls (EC50 = 0.41 ± 0.15 μM). The results provide a direct evidence of an apparent normal functional activity of brain μ-opioid receptors (Gi/Go-protein coupling) during the opioid dependence process in humans. The data also demonstrate a functional uncoupling of α2-adrenoceptors from G-proteins, which indicates a heterologous desensitization of these receptors. This finding could represent an adaptive mechanism against the decreased noradrenergic activity induced by the chronic presence of opioid drugs.

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Acknowledgements

This study was supported by grants from the FNSRS (32-57066.99), Switzerland to JAG-S, the Basque Government (PI-98/8) and the University of the Basque Country (G13/98) Spain to JJM. JG-M was supported by a fellowship from the MEC, Madrid, Spain. The authors wish to thank the Institutes of Forensic Medicine of Geneva (Dr R La Harpe) and Bilbao (Dr R Alcaraz) for their cooperation in the study. JAG-S is a member of the Institut d'Estudis Catalans (Barcelona, Spain).

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  1. Department of Psychiatry, Faculty of Medicine, University of Geneva, HUG, Hôpital Belle-Idée, Chêne-Bourg, CH-1225, Switzerland

    J J Meana, J A García-Sevilla & J Guimón

  2. Department of Pharmacology, University of the Basque Country, Leioa, E-48940, Bizkaia, Spain

    J J Meana & J González-Maeso

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Meana, J., González-Maeso, J., García-Sevilla, J. et al. μ-Opioid receptor and α2-adrenoceptor agonist stimulation of [35S]GTPγS binding to G-proteins in postmortem brains of opioid addicts. Mol Psychiatry 5, 308–315 (2000). https://doi.org/10.1038/sj.mp.4000727

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