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
- Year
- 2004
- Journal
- Brain research. Molecular brain research
- PMID
- 14969742
- DOI
- 10.1016/j.molbrainres.2003.11.009
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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| Molecular Genetics and New Medication Strategies for Opioid Addiction. | Hurd YL et al. | — | 2018 | → |
| Arresting the Development of Addiction: The Role of <i>β</i>-Arrestin 2 in Drug Abuse. | Porter-Stransky KA et al. | — | 2017 | → |
| Pharmacoepigenomics of opiates and methadone maintenance treatment: current data and perspectives. | Marie-Claire C et al. | — | 2017 | → |
| Upregulation of IRAS/nischarin (I<sub>1</sub>-imidazoline receptor), a regulatory protein of μ-opioid receptor trafficking, in postmortem prefrontal cortex of long-term opiate and mixed opiate/cocaine abusers. | Keller B et al. | — | 2017 | → |
| KAT2B polymorphism identified for drug abuse in African Americans with regulatory links to drug abuse pathways in human prefrontal cortex. | Johnson EO et al. | — | 2016 | → |
| Neuronal extracellular signal-regulated kinase (ERK) activity as marker and mediator of alcohol and opioid dependence. | Zamora-Martinez ER et al. | — | 2014 | → |
| Patterns of cortical activation following motor tasks and psychological-inducing movie cues in heroin users: an fMRI study. | Jiang YL et al. | — | 2014 | → |
| Reduced responses to heroin-cue-induced craving in the dorsal striatum: effects of long-term methadone maintenance treatment. | Wang Y et al. | — | 2014 | → |
| ELK1 transcription factor linked to dysregulated striatal mu opioid receptor signaling network and OPRM1 polymorphism in human heroin abusers. | Daws SE et al. | — | 2013 | → |
| G-protein-coupled receptor kinase 2 and hypertension: molecular insights and pathophysiological mechanisms. | Santulli G et al. | — | 2013 | → |
| Molecular and cellular mechanisms of the age-dependency of opioid analgesia and tolerance. | Zhao J et al. | — | 2012 | → |
| Construction of the subtracted cDNA library of striatal neurons treated with long-term morphine. | Bai B et al. | — | 2011 | → |
| Molecular adaptations of apoptotic pathways and signaling partners in the cerebral cortex of human cocaine addicts and cocaine-treated rats. | Alvaro-Bartolomé M et al. | — | 2011 | → |
| alpha-Tocopherol decreases the somatostatin receptor-effector system and increases the cyclic AMP/cyclic AMP response element binding protein pathway in the rat dentate gyrus. | Hernández-Pinto AM et al. | — | 2009 | → |
| Down-regulation of c-Cbl by morphine accounts for persistent ERK1/2 signaling in delta-opioid receptor-expressing HEK293 cells. | Eisinger DA et al. | — | 2009 | → |
| Genetic modulation of the pharmacological treatment of pain. | Lötsch J et al. | — | 2009 | → |
| Modulation of opioid receptor function by protein-protein interactions. | Alfaras-Melainis K et al. | — | 2009 | → |
| Chronic ethanol exposure increases the association of hippocampal mu-opioid receptors with G-protein receptor kinase 2. | Saland LC et al. | — | 2008 | → |
| Effects of chronic morphine and morphine withdrawal on gene expression in rat peripheral blood mononuclear cells. | Desjardins S et al. | — | 2008 | → |
| Brain opioid receptor binding in early abstinence from opioid dependence: positron emission tomography study. | Williams TM et al. | — | 2007 | → |
| Physiological roles of G protein-coupled receptor kinases and arrestins. | Premont RT et al. | — | 2007 | → |
| RGS14 prevents morphine from internalizing Mu-opioid receptors in periaqueductal gray neurons. | Rodríguez-Muñoz M et al. | — | 2007 | → |
| Street heroin induces mitochondrial dysfunction and apoptosis in rat cortical neurons. | Cunha-Oliveira T et al. | — | 2007 | → |
| Functional interaction between alpha2-adrenoceptors, mu- and kappa-opioid receptors in the guinea pig myenteric plexus: effect of chronic desipramine treatment. | Canciani L et al. | — | 2006 | → |
| [GRKs and arrestins: the therapeutic pathway?]. | Métayé T et al. | — | 2006 | → |
| Endogenous opiates and behavior: 2004. | Bodnar RJ et al. | — | 2005 | → |
| Mu opioid receptor regulation and opiate responsiveness. | Raehal KM et al. | — | 2005 | → |
| Pathophysiological roles of G-protein-coupled receptor kinases. | Métayé T et al. | — | 2005 | → |
| Long-term regulation of signalling components of adenylyl cyclase and mitogen-activated protein kinase in the pre-frontal cortex of human opiate addicts. | Ferrer-Alcón M et al. | — | 2004 | → |