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

• Published in: Molecular psychiatry Vol. 5; no. 3; pp. 308 - 315
• Main Authors: MEANA, J. J, GONZALEZ-MAESO, J, GARCIA-SEVILLA, J. A, GUIMON, J
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.05.2000
• Subjects: Addicts; Adrenergic receptors; Adult and adolescent clinical studies; Agonists; Binding sites; Biological and medical sciences; Brain; Drug abuse; Drug addictions; Drug dependence; Enkephalins; Heroin; Medical sciences; Miscellaneous; Narcotics; Norepinephrine; Opioid receptors; Proteins; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Toxicology; Human; α2-Adrenergic receptor; Drug addiction; Agonist; Pathogenesis; Postmortem; μ Opioid receptor; Exploration; Opiates; Binding site; Selectivity; Frontal cortex; Mechanism; Dependence; Drug of abuse; Adrenergic receptor; Brain (vertebrata); G protein
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/sj.mp.4000727

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.