title: Differential regulation of beta-arrestin 1 and beta-arrestin 2 gene expression in rat brain by morphine.
abstract: Beta-arrestins are a family of regulatory and scaffold proteins functioning in signal transduction of G protein-coupled receptors including opioid receptors. Upon agonist stimulation, beta-arrestins bind to opioid receptors phosphorylated by G protein-coupled receptor kinases and promote receptor internalization and desensitization. Studies indicated that beta-arrestins are required in the development of morphine tolerance in mice. In the current study, we investigated the potential regulatory effects of morphine administration on beta-arrestin 1 and beta-arrestin 2 mRNA levels in different brain regions in rat using in situ hybridization method. Our results showed that the acute morphine administration (10 mg/kg) resulted in approximately 30% reduction in both beta-arrestin 1 and beta-arrestin 2 mRNA levels in hippocampus while the chronic morphine treatment (10 mg/kg, b.i.d., for 9 days) caused no significant change in level of either beta-arrestin mRNA. In locus coeruleus, both acute and chronic morphine treatments resulted in significant decreases (over 50%) in beta-arrestin 1 mRNA level but failed to induce any change in the level of beta-arrestin 2 gene expression. The acute morphine administration had no significant effect on beta-arrestin 1 or beta-arrestin 2 mRNA level in periaqueductal gray and cerebral cortex. However, after chronic morphine treatment, beta-arrestin 2 mRNA level decreased by 40% in periaqueductal gray and increased by 25% in cerebral cortex, in strong contrast to the unchanged beta-arrestin 1 mRNA level in these two brain regions. Furthermore, spontaneous or naloxone-precipitated withdrawal of morphine that did not affect the level of beta-arrestin 1 mRNA resulted in an aberrant increase (100% over control) in beta-arrestin 2 mRNA level in hippocampus. Our results thus demonstrated for the first time that opiate administration regulates level of beta-arrestin mRNAs in brain and the expression of beta-arrestin 1 and beta-arrestin 2 subtypes is differentially regulated in locus coeruleus, periaqueductal gray, and cerebral cortex by morphine. These data suggest that beta-arrestin 1 and beta-arrestin 2 may play different roles in the development of opioid tolerance and dependence.
authors.affiliation: National Laboratory of Medical Neurobiology, Fudan University Medical Center, 138 Yi Xue Yuan Road, Shanghai 200032, People's Republic of China.
authors.forename: X L
authors.initials: XL
authors.lastname: Fan
authors.forename: J S
authors.initials: JS
authors.lastname: Zhang
authors.forename: X Q
authors.initials: XQ
authors.lastname: Zhang
authors.forename: W
authors.initials: W
authors.lastname: Yue
authors.forename: L
authors.initials: L
authors.lastname: Ma
mesh_terms: D000818:Animals; D019390:Arrestins / Q000096:biosynthesis*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605255:Arrb1 protein, mouse; C000605256:Arrb1 protein, rat; C000605258:Arrb2 protein, mouse; C000605257:Arrb2 protein, rat; D019390:Arrestins; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D009020:Morphine