mu-opioid receptor and alpha2-adrenoceptor agonist stimulation of [35S]GTPgammaS binding to G-proteins in postmortem brains of opioid addicts.
Repeated opioid administration has been associated in human brain with unaltered density of mu-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]GTPgammaS binding was quantified in postmortem prefrontal cortices of 15 opioid-dependent subjects and 15 matched controls. The stimulation of [35S]GTPgammaS binding by the mu-opioid receptor agonist DAMGO or the alpha2-adrenoceptor agonist UK14304 was used as a functional measure of the status of the receptor-G-protein coupling. [35S]GTPgammaS 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]GTPgammaS binding stimulation by DAMGO showed a maximal effect (62+/-8%) and a potency (EC50 = 1.09+/-0.26 microM) that did not differ from the maximal effect (60+/-12%) and potency (EC50 = 2.01+/-0.58 microM) in controls. In opioid addicts, [35S]GTPgammaS 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 microM) when compared with controls (EC50 = 0.41+/-0.15 microM). The results provide a direct evidence of an apparent normal functional activity of brain mu-opioid receptors (Gi/Go-protein coupling) during the opioid dependence process in humans. The data also demonstrate a functional uncoupling of alpha2-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.
Meana
J J
JJ
Department of Psychiatry, Faculty of Medicine, University of Geneva, HUG, Hôpital Belle-Idée, CH-1225 Chêne-Bourg, Switzerland. kfpmemaj@lg.ehu.es
González-Maeso
J
J
García-Sevilla
J A
JA
Guimón
J
J
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000328:Adult; D001344:Autopsy; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000068438:Brimonidine Tartrate; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism*; D006801:Humans; D008297:Male; D009293:Opioid-Related Disorders / Q000378:metabolism* / Q000473:pathology; D011180:Postmortem Changes; D011810:Quinoxalines / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012016:Reference Values; D013462:Sulfur Radioisotopes
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D011810:Quinoxalines; D017450:Receptors, Opioid, mu; D013462:Sulfur Radioisotopes; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000068438:Brimonidine Tartrate; D019204:GTP-Binding Proteins