Decreased immunodensities of micro-opioid receptors, receptor kinases GRK 2/6 and beta-arrestin-2 in postmortem brains of opiate addicts

Brain Res Mol Brain Res. 2004 Feb 5;121(1-2):114-22. 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Arrestins / metabolism*
  • Case-Control Studies
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Female
  • G-Protein-Coupled Receptor Kinases
  • Humans
  • Immunoblotting / methods
  • Male
  • Methadone / adverse effects
  • Middle Aged
  • Opioid-Related Disorders / metabolism*
  • Postmortem Changes
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptors, Opioid, mu / metabolism*
  • beta-Adrenergic Receptor Kinases
  • beta-Arrestin 2
  • beta-Arrestins


  • ARRB2 protein, human
  • Arrestins
  • Receptors, Opioid, mu
  • beta-Arrestin 2
  • beta-Arrestins
  • Protein-Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • beta-Adrenergic Receptor Kinases
  • G-Protein-Coupled Receptor Kinases
  • G-protein-coupled receptor kinase 6
  • Methadone