Acute and chronic morphine treatments and morphine withdrawal differentially regulate GRK2 and GRK5 gene expression in rat brain.
Opioid agonist stimulates activation of G protein-coupled receptor kinase (GRK) and causes desensitization of opioid signaling, which plays an important role in opioid tolerance. The current study investigated the potential regulatory effects of acute and chronic morphine administration and withdrawal on GRK2 and GRK5 gene expression in rat brain. Our results showed that the initial morphine treatment (10 mg/kg) significantly increased GRK mRNA levels in cerebral cortex, hippocampus, and lateral thalamic nuclei. A significant decrease in GRK5 mRNA levels was observed in periaqueductal gray. In strong contrast, repeated administration of morphine for 9 days failed to cause any significant increase in GRK5 mRNA in any of these brain regions. Chronic morphine treatment resulted in 30-70% down-regulation of GRK2 expression in cerebral cortex, hippocampus, thalamus, and locus coeruleus, opposite to what observed with the single morphine administration. Moreover, spontaneous and naloxone-precipitated morphine withdrawal resulted in aberrant increases in GRK2 and GRK5 mRNA levels in these brain regions. Taken together, our study suggests that opioid not only induces rapid negative feedback regulation on opioid signals through activation of GRK but also exerts its impact, via controlling levels of GRK gene expression, on the regulatory machinery itself over a longer period of time in brain.
Fan
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X
National Laboratory of Medical Neurobiology, Fudan University Medical Center, 138 Yi Xue Yuan Road, Shanghai 200032, People's Republic of China.
Zhang
J
J
Zhang
X
X
Yue
W
W
Ma
L
L
D000701:Analgesics, Opioid / Q000009:adverse effects* / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects* / Q000235:genetics*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D004076:Digoxigenin / Q000494:pharmacology; D054769:G-Protein-Coupled Receptor Kinase 2; D054774:G-Protein-Coupled Receptor Kinase 5; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D008297:Male; D009020:Morphine / Q000009:adverse effects* / Q000494:pharmacology*; D015345:Oligonucleotide Probes; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D051552:beta-Adrenergic Receptor Kinases
D000701:Analgesics, Opioid; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D009020:Morphine; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; C496568:GRK2 protein, mouse; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D054774:G-Protein-Coupled Receptor Kinase 5; C517895:Grk5 protein, mouse; C517897:Grk5 protein, rat; D004076:Digoxigenin