REGULATION OF G-PROTEIN-COUPLED RECEPTOR KINASE-2 IN BRAINS OF OPIATE-TREATED RATS AND HUMAN OPIATE ADDICTS

The effects of opiate drugs (heroin, morphine, and methadone) on the l evels of G protein-coupled receptor kinase 2 (GRK2) were studied in ra t and human brain frontal cortices. The density of brain GRK2 was meas ured by immunoblot assays in acute and chronic opiate-treated rats as well as in opiate-dependent rats after spontaneous or naloxone-precipi tated withdrawal and in human opiate addicts who had died of an opiate overdose. In postmortem brains from human addicts, total GRK2 immunor eactivity was not changed significantly, but the level of the membrane -associated kinase was modestly but significantly increased (12%) comp ared with matched controls. In rats treated chronically with morphine or methadone modest increases of the enzyme levels (only significant a fter methadone) were observed. Acute treatments with morphine and meth adone induced dose-and time-dependent increases (8-22%) in total GRK2 concentrations [higher increases were observed for the membrane-associ ated enzyme (46%)]. Spontaneous and naloxone-precipitated withdrawal a fter chronic morphine or methadone induced a marked up-regulation in t he levels of total GRK2 in the rat frontal cortex (18-25%). These resu lts suggest that GRK2 is involved in the short-term regulation of mu-o pioid receptors in vivo and that the activity of this regulatory kinas e in brain could have a relevant role in opiate tolerance, dependence, and withdrawal.