Regulation of RGS proteins by chronic morphine in rat locus coeruleus

Gold, Stephen J.; Han, Ming–Hu; Herman, Amy E.; Yan, Ni; Pudiak, Cindy M.; Aghajanian, George K.; Liu, Rong-Jian; Potts, Bryan W.; Mumby, Susanne M.; Nestler, Eric J.

doi:10.1046/j.1460-9568.2003.02529.x

Cited by 94 publications

(77 citation statements)

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“…Regulator of G protein signaling 4 (Rgs4) is a 28-kDa protein known to control postreceptor signaling cascades for numerous G protein-coupled receptors (GPCRs), including dopamine, serotonin, adrenergic, muscarinic, and mu and delta opioid receptors (2)(3)(4)(5)(6)(7)(8)(9). Rgs4 is generally thought to be a negative modulator of Gα subunits by promoting their hydrolysis of GTP and by antagonizing the regulation of their effectors, although the actions of Rgs proteins are more complex, because they can either inhibit or facilitate several actions of their associated receptors (10,11).…”

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confidence: 99%

Regulator of G protein signaling 4 is a crucial modulator of antidepressant drug action in depression and neuropathic pain models

Stratinaki

Varidaki

Mitsi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Regulator of G protein signaling 4 (Rgs4) is a signal transduction protein that controls the function of monoamine, opiate, muscarinic, and other G protein-coupled receptors via interactions with Gα subunits. Rgs4 is expressed in several brain regions involved in mood, movement, cognition, and addiction and is regulated by psychotropic drugs, stress, and corticosteroids. In this study, we use genetic mouse models and viral-mediated gene transfer to examine the role of Rgs4 in the actions of antidepressant medications. We first analyzed human postmortem brain tissue and found robust up-regulation of RGS4 expression in the nucleus accumbens (NAc) of subjects receiving standard antidepressant medications that target monoamine systems. Behavioral studies of mice lacking Rgs4 , including specific knockdowns in NAc, demonstrate that Rgs4 in this brain region acts as a positive modulator of the antidepressant-like and antiallodynic-like actions of several monoamine-directed antidepressant drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and norepinephrine reuptake inhibitors. Studies using viral-mediated increases in Rgs4 activity in NAc further support this hypothesis. Interestingly, in prefrontal cortex, Rgs4 acts as a negative modulator of the actions of nonmonoamine-directed drugs that are purported to act as antidepressants: the N-methyl-D-aspartate glutamate receptor antagonist ketamine and the delta opioid agonist (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide. Together, these data reveal a unique modulatory role of Rgs4 in the brain region-specific actions of a wide range of antidepressant drugs and indicate that pharmacological interventions at the level of RGS4 activity may enhance the actions of such drugs used for the treatment of depression and neuropathic pain.

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mentioning

confidence: 99%

Regulator of G protein signaling 4 is a crucial modulator of antidepressant drug action in depression and neuropathic pain models

Stratinaki

Varidaki

Mitsi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…For all studies, four groups of animals were used: (1) sham-saline (control), (2) morphinesaline (chronic morphine), (3) sham-naltrexone (naltrexone), and (4) morphine-naltrexone (withdrawal). These treatment conditions were based on substantial evidence for their ability to induce high levels of morphine dependence in the chronic morphine condition and high levels of opiate withdrawal in the withdrawal condition (Shaw-Lutchman et al, 2002;Gold et al, 2003).…”

Section: Methodsmentioning

confidence: 99%

“…Brains were removed and punches were taken from the LC or VTA as described previously (Fitzgerald et al, 1996;Gold et al, 2003). The tissue was then immediately frozen.…”

Section: Methodsmentioning

confidence: 99%

“…Four hours later, brains were removed and frozen. Tissue was sectioned in a cryostat at 12 m. RNA probes for prodynorphin and FKBP5 were prepared and labeled with 35 S by incorporation during in vitro transcription using T7 RNA polymerase as described previously (Gold et al, 2003). Tissue sections were fixed in 4% paraformaldehyde, washed, acetylated, dehydrated, and incubated with probe (10 ϫ 10 6 cpm/ml) in hybridization buffer (20 mM Tris-HCl, pH 7.5, 1 mM EDTA, 1ϫ Denhardt's solution, 335 mM NaCl, 50% deionized formamide, 10% dextran sulfate, 0.3 mg/ml salmon sperm DNA, 0.15 mg/ml yeast tRNA, and 80 mM DTT, in DEPC-H 2 0) overnight at 60°C.…”

Section: Methodsmentioning

confidence: 99%

“…The following day, sections were washed in progressively less concentrated SSC buffers (4ϫ, 2ϫ, 0.5ϫ, and 0.1ϫ) containing 10 mM sodium thiosulfate, treated with RNase A, dried, and exposed to film. Levels of RNA were quantified by densitometry using NIH Image as described previously (Gold et al, 2003).…”

Section: Methodsmentioning

confidence: 99%

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Regulation of Gene Expression by Chronic Morphine and Morphine Withdrawal in the Locus Ceruleus and Ventral Tegmental Area

McClung¹,

Nestler²,

Zachariou³

2005

J. Neurosci.

149

137

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Morphine dependence is associated with long-term adaptive changes in the brain that involve gene expression. Different behavioral effects of morphine are mediated by different brain regions, for example, the locus ceruleus (LC), a noradrenergic nucleus, is implicated in physical dependence and withdrawal, whereas the ventral tegmental area (VTA), a dopaminergic nucleus, contributes to rewarding and locomotor responses to the drug. However, the global changes in gene expression that occur in these brain regions after morphine exposure and during withdrawal remain unknown. Using DNA microarray analysis in both mice and rats, we now characterize gene expression changes that occur in these brain regions with chronic morphine and antagonist-precipitated withdrawal. In the LC, numerous genes display common regulation between mouse and rat, including tyrosine hydroxylase, prodynorphin, and galanin. Furthermore, we identify clusters of genes that are regulated similarly by chronic morphine and by withdrawal, as well as clusters that show opposite regulation under these two conditions. Interestingly, most gene expression changes that occur in the VTA in response to chronic morphine are different from those seen in the LC, but the gene expression patterns in the two brain regions are very similar after withdrawal. In addition, we examined two genes (prodynorphin and FK506 binding protein 5) that are strongly regulated by chronic morphine or morphine withdrawal in the LC for their role in regulating withdrawal-associated behaviors. Inhibition of either protein profoundly affects withdrawal responses, demonstrating that the genes identified in this study have important functional roles in mediating opiate-induced behaviors.

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Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia

Smith¹,

Maixner

Fillingim

et al. 2012

Arthritis & Rheumatism

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Objective Fibromyalgia (FM) represents a complex disorder characterized by widespread pain and tenderness and frequently accompanied by additional somatic and cognitive/affective symptoms. Genetic risk factors are known to contribute to the etiology of the syndrome, but few specific genetic variants have been identified to date and still require replication. In this study, a large scale candidate gene approach was used to examine over 350 genes for association with FM. Methods Four hundred ninety-six FM patients were included in the study as cases with a total of 348 chronic pain-free controls. Genotyping was performed using a dedicated gene array chip, the Pain Research Panel, which assays variants characterizing over 350 genes known to be involved in biological pathways relevant to nociception, inflammation, and mood. Association testing was performed using logistic regression. Results Significant differences in allele frequencies between cases and controls were observed for three genes: GABRB3 (rs4906902, p = 3.65×10−6), TAAR1 (rs8192619, p = 1.11×10−5) and GBP1 (rs7911, p = 1.06×10−4). These three genes, and seven other genes with suggestive evidence for association, were examined in a second, independent cohort of FM patients and controls genotyped using the Perlegen 600K platform. Evidence of association in the replication cohort was observed for TAAR1, RGS4, CNR1, and GRIA4 genes. Conclusion Variation in these genes may serve as a basis for development of new diagnostic approaches, and these genes’ products may contribute to the pathophysiology of FM and represent potential targets for therapeutic action.

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Regulation of RGS proteins by chronic morphine in rat locus coeruleus

Cited by 94 publications

References 59 publications

Regulator of G protein signaling 4 is a crucial modulator of antidepressant drug action in depression and neuropathic pain models

Regulator of G protein signaling 4 is a crucial modulator of antidepressant drug action in depression and neuropathic pain models

Regulation of Gene Expression by Chronic Morphine and Morphine Withdrawal in the Locus Ceruleus and Ventral Tegmental Area

Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia

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