Regulation of G Protein‐Coupled Receptor Kinase 2 in Brains of Opiate‐Treated Rats and Human Opiate Addicts

Abstract

The effects of opiate drugs (heroin, morphine, and methadone) on the levels of G protein‐coupled receptor kinase 2 (GRK2) were studied in rat and human brain frontal cortices. The density of brain GRK2 was measured by immunoblot assays in acute and chronic opiate‐treated rats as well as in opiate‐dependent rats after spontaneous or naloxone‐precipitated withdrawal and in human opiate addicts who had died of an opiate overdose. In postmortem brains from human addicts, total GRK2 immunoreactivity was not changed significantly, but the level of the membrane‐associated kinase was modestly but significantly increased (12%) compared with matched controls. In rats treated chronically with morphine or methadone modest increases of the enzyme levels (only significant after methadone) were observed. Acute treatments with morphine and methadone induced dose‐ and time‐dependent increases (8–22%) in total GRK2 concentrations [higher increases were observed for the membrane‐associated enzyme (46%)]. Spontaneous and naloxone‐precipitated withdrawal after chronic morphine or methadone induced a marked up‐regulation in the levels of total GRK2 in the rat frontal cortex (18–25%). These results suggest that GRK2 is involved in the short‐term regulation of μ‐opioid receptors in vivo and that the activity of this regulatory kinase in brain could have a relevant role in opiate tolerance, dependence, and withdrawal.

Morphine Tolerance and Physical Dependence Are Altered in Conditional HIV-1 Tat Transgenic Mice

“…The 75-mg morphine pellets result in initial blood levels of 2 mg/ml of morphine and in sustained blood levels (0.6 mg/ml morphine) by 48 hours that last 2-5 days (Bryant et al, 1988). The levels of opiates in the blood of addicts who had died of an opiate overdose indicate an average level of opiates in the blood of 0.8 6 0.1 mg/ml (Ozaita et al, 1998), similar to that seen in 75-mg morphine-pelleted mice (Bryant et al, 1988). We realize that the use of a pellet to administer morphine chronically to mice differs from how humans chronically abuse the drug, but in both cases sufficiently high morphine brain levels are achieved to develop tolerance.…”

“…Using morphine pellets is a standard method for continuously administering morphine to prevent cycles of withdrawal in mice, and it produces brain drug levels considered to be similar to blood/tissue levels achieved in humans who are tolerant and dependent on opiates (Ozaita et al, 1998;Ghazi-Khansari et al, 2006), and therapeutic levels seen in patients maintained on chronic opiates/ opiate pumps for intractable pain (Balch and Trescot, 2010).…”

Desensitization of G Protein–coupled Receptors and Neuronal Functions

“…Furthermore, both acute and chronic treatment with opioid drugs as well as opioid withdrawal induce an increase in GRK2 levels in the rat cerebral cortex in experimental animals, and membraneassociated GRK2 levels are increased in brains of human opioid addicts (Ozaita et al 1998). GRK2 immunoreactivity was increased in the cortex of rats treated with opioids and rendered tolerant to the antinociceptive effect of opioids (Hurle 2001).…”

Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia

“…The concentrations of arrestin/GRKs in cultured cells and in vivo are altered by drugs that directly or indirectly cause persistent stimulation or blockade of GPCRs [7,22,25,29,42,45,72,80,99], which implies the involvement of signaling mechanism in the regulation of the arrestin/GRK expression. The concentration GRK2, a short-lived protein, is regulated by synthesis as well as degradation, both of which are responsive to various signaling pathways (reviewed in [85,86]).…”