Decreased immunodensities of micro-opioid receptors, receptor kinases GRK 2/6 and beta-arrestin-2 in postmortem brains of opiate addicts. |
| Authors: |
Ferrer-Alcón, Marcel La Harpe, Romano García-Sevilla, Jesús A
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| Citation: |
Ferrer-Alcón M, etal., Brain Res Mol Brain Res. 2004 Feb 5;121(1-2):114-22. doi: 10.1016/j.molbrainres.2003.11.009. |
| RGD ID: |
401901596 |
| Pubmed: |
PMID:14969742 (View Abstract at PubMed) |
| DOI: |
DOI:10.1016/j.molbrainres.2003.11.009 (Journal Full-text) |
The homologous regulation of opioid receptors, through G protein-coupled receptor kinases (GRKs) and beta-arrestins, is an initial step in the complex molecular mechanisms leading to opiate tolerance and dependence. This study was designed to evaluate in parallel the contents of immunolabeled micro-opioid receptors (glycosylated proteins), two representative GRKs (GRK 2 and GRK 6) and beta-arrestin-2 in brains of opiate addicts who had died of an opiate overdose (heroin or methadone). The immunodensities of micro-opioid receptors were decreased (66 kDa protein: 24%, n=24, P<0.0001; 85 kDa protein: 16%, n=24, P<0.05) in the prefrontal cortex of opiate addicts compared with sex-, age-, and PMD-matched controls. This down-regulation of brain micro-opioid receptors was more pronounced in opiate addicts dying of a heroin overdose (27-30%, n=13) than in those who died of a methadone overdose (5-16%, n=11). In the same brains, significant decreases in the immunodensities of GRK 2 (19%, n=24, P<0.05), GRK 6 (25%, n=24, P<0.002) and beta-arrestin-2 (22%, n=24, P< 0.0005) were also quantitated. In contrast, the content of alpha-internexin (a neuronal marker used as a negative control) was not changed in brains of opiate addicts. In these subjects, there was a significant correlation between the densities of GRK 6 and beta-arrestin-2 (r=0.63, n=24, P=0.001), suggesting that both proteins are regulated in a coordinated manner by opiate drugs in the brain. The results indicate that opiate addiction in humans (tolerant state) is associated with down-regulation of brain micro-opioid receptors and regulatory GRK 2/6 and beta-arrestin-2 proteins. These molecular adaptations may be relevant mechanisms for the induction of opiate tolerance in brains of opiate addicts.
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| Genes (Rattus norvegicus) |
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| Arrb2 (arrestin, beta 2) | Grk2 (G protein-coupled receptor kinase 2) | Grk6 (G protein-coupled receptor kinase 6) | | Oprm1 (opioid receptor, mu 1) |
| Genes (Mus musculus) |
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| Arrb2 (arrestin, beta 2) | Grk2 (G protein-coupled receptor kinase 2) | Grk6 (G protein-coupled receptor kinase 6) | | Oprm1 (opioid receptor, mu 1) |
| Genes (Homo sapiens) |
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| ARRB2 (arrestin beta 2) | GRK2 (G protein-coupled receptor kinase 2) | GRK6 (G protein-coupled receptor kinase 6) | | OPRM1 (opioid receptor mu 1) |
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