Downregulation of brain mineralocorticoid and glucocorticoid receptor by antisense oligodeoxynucleotide treatment fails to alter spatial navigation in rats

Engelmann, Mario; Landgraf, Rainer; Lörscher, Patrick; Conzelmann, Charlotte; Probst, Joseph Christopher; Holsboer, Florian; Reul, Johannes M. H. M.

doi:10.1016/s0014-2999(98)00702-x

Cited by 16 publications

(16 citation statements)

References 38 publications

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“…The glucocorticoid receptor antisense oligodeoxynucleotide (ODN) sequence: 5Ј-TGG AGT CCA TTG GCA AAT-3Ј was directed against the translation initiation site of the rat mRNA (Engelmann et al, 1998) (GenBank accession number Y12264). The mismatch ODN sequence was designed by mismatching five bases (Engelmann et al, 1998) (denoted here by boldface type) of the antisense sequence, 5Ј-TGA AGT TCA GTG TCA ACT-3Ј. A BLAST search was performed to check for the theoretical specificity and activity of the sequences, to confirm that they were not homologous to other sequences in the rat.…”

Section: Methodsmentioning

confidence: 99%

Stress Induces a Switch of Intracellular Signaling in Sensory Neurons in a Model of Generalized Pain

Khasar¹,

Burkham²,

Dina³

et al. 2008

J. Neurosci.

159

169

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Stress dramatically exacerbates pain in diseases such as fibromyalgia and rheumatoid arthritis, but the underlying mechanisms are unknown. We tested the hypothesis that stress causes generalized hyperalgesia by enhancing pronociceptive effects of immune mediators. Rats exposed to nonhabituating sound stress exhibited no change in mechanical nociceptive threshold, but showed a marked increase in hyperalgesia evoked by local injections of prostaglandin E 2 or epinephrine. This enhancement, which developed more than a week after exposure to stress, required concerted action of glucocorticoids and catecholamines at receptors located in the periphery on sensory afferents. The altered response to pronociceptive mediators involved a switch in coupling of their receptors from predominantly stimulatory to inhibitory G-proteins (G s to G i ), and for prostaglandin E 2 , emergence of novel dependence on protein kinase C. Thus, an important mechanism in generalized pain syndromes may be stress-induced coactivation of the hypothalamo-pituitary-adrenal and sympathoadrenal axes, causing a long-lasting alteration in intracellular signaling pathways, enabling normally innocuous levels of immune mediators to produce chronic hyperalgesia.

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Section: Methodsmentioning

confidence: 99%

Stress Induces a Switch of Intracellular Signaling in Sensory Neurons in a Model of Generalized Pain

Khasar¹,

Burkham²,

Dina³

et al. 2008

J. Neurosci.

159

169

View full text Add to dashboard Cite

show abstract

“…For the experiment with GR oligodeoxynucleotides (ONDs), sequences for antisense, sense, and mixed-base ONDs were chosen on the basis of previous studies (Engelmann et al, 1998;Wang et al, 2004;Lim et al, 2005b,c). The sequences overlapping the respective initiation codon (GenBank accession number M14053) used to target the rat's GR mRNA were as follows: antisense (TGGAGTCCATTGGCAAAT), sense (ATTTGCCAATGGACTCCA), and mixed base (TGAAGTTCAGTGT-CAACT).…”

Section: Methodsmentioning

confidence: 99%

Expression of Spinal NMDA Receptor and PKCγ after Chronic Morphine Is Regulated by Spinal Glucocorticoid Receptor

Lim

Wang²,

Zeng³

et al. 2005

J. Neurosci.

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Spinal NMDA receptor (NMDAR), protein kinase C (PKC), and glucocorticoid receptor (GR) have all been implicated in the mechanisms of morphine tolerance; however, how these cellular elements interact after chronic morphine exposure remains unclear. Here we show that the expression of spinal NMDAR and PKC␥ after chronic morphine is regulated by spinal GR through a cAMP response elementbinding protein (CREB)-dependent pathway. Chronic morphine (10 g, i.t.; twice daily for 6 d) induced a time-dependent upregulation of GR, the NR1 subunit of NMDAR, and PKC␥ within the rat's spinal cord dorsal horn. This NR1 and PKC␥ upregulation was significantly diminished by intrathecal coadministration of morphine with the GR antagonist RU38486 or a GR antisense oligodeoxynucleotide. Intrathecal coadministration of morphine with an adenylyl cyclase inhibitor (2Ј,5Ј-dideoxyadenosine) or a protein kinase A inhibitor (H89) also significantly attenuated morphine-induced NR1 and PKC␥ expression, whereas intrathecal treatment with an adenylyl cyclase activator (forskolin) alone mimicked morphine-induced expression of GR, NR1, and PKC␥. Moreover, the expression of phosphorylated CREB was upregulated within the spinal cord dorsal horn after chronic morphine, and a CREB antisense oligodeoxynucleotide coadministered intrathecally with morphine prevented the upregulation of GR, NR1, and PKC␥. These results indicate that spinal GR through the cAMP-CREB pathway played a significant role in NMDAR and PKC␥ expression after chronic morphine exposure. The data suggest that genomic interaction among spinal GR, NMDAR, and PKC␥ may be an important mechanism that contributes to the development of morphine tolerance.

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Section: Ligand Specificity Of the Mrmentioning

confidence: 99%

“…Expression of 11 ␤ -HSD2 in the brain is limited and restricted to a few circumventricular nuclei and select neurons of the nucleus tractus solitarii [31][32][33][34] . The highest concentrations of MR in the hippocampus, where they are not coexpressed with 11 ␤ -HSD2, thus are bound primarily by glucocorticoids [35][36][37] .Notwithstanding limited 11 ␤ -HSD2 expression in the brain, in vitro incubation of rat brain minces with tritiated corticosterone indicates that it is efficiently converted to the inactive steroid 11-dehydrocorticosterone [38,39] . Moreover, intracerebroventricular infusions of 11 ␤ -HSD inhibitors produces hypertension, and the intracerebroventricular infusion of an MR antagonist abrogates the hypertension produced by the systemic administration of these inhibitors [11,40,41] .…”

mentioning

confidence: 99%

“…Aldosterone, but not corticosterone, activates MR in circumventricular areas associated with blood pressure control to increase blood pressure [62] . Aldosterone replacement in the adrenalectomized animal does not restore normal corticosterone-mediated functions of the hippocampal MR, including modulation of arousal and stress responses and some forms of memory and cognitive functions [35][36][37] .The area of study with perhaps the greatest potential of finding mechanisms for both ligand-and cell-specific functions of the MR is the differential distribution of proteins that interact with steroid receptors. Chaperone proteins, coactivators and corepressors, underlie diversity and cell specificity of other steroid-receptor-mediated signals; however, little is known about the transcriptional modulation of the MR.…”

mentioning

confidence: 99%

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Central Mineralocorticoid Receptors and Cardiovascular Disease

Gómez-Sánchez¹

2012

Endocrine Hypertension

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sodium and water by the kidneys [8] became commonly accepted as solely responsible for the hypertension produced by mineralocorticoid + salt excess. Mineralocorticoid Receptors in the Brain Mediate Hemodynamic EffectsThe demonstration of specific binding of aldosterone in select areas of the brain, as well as the heart and vessels [9] , and the finding that the ablation of the anteroventral area of the third ventricle abrogated mineralocorticoid + salt, renovascular and Dahl salt-sensitive (SS) rat hypertension [for a review, see 10 ] kindled interest in the central hemodynamic effects of mineralocorticoids. Selective infusions of mineralocorticoid receptor (MR) agonists and antagonists in various animal models of hypertension confirmed that MR of the circumventricular organs were crucial for the development of several models of hypertension and that activation of MR in the amygdala increased salt appetite [for a review, see 11 ]. Mineralocorticoid Excess Mediates Inflammation and Structural Changes in the Heart, Vessels and KidneysPatients with primary aldosteronism have cardiac hypertrophy compared to patients with essential hypertension who have similar levels of hypertension for the same duration [12,13] . Studies in experimental animals sug- Key WordsMineralocorticoid receptor ؒ Cardiovascular disease ؒ Addison disease, rat model AbstractThe mineralocorticoid receptor (MR) is expressed in many cell types throughout the body, including specific neurons, and mediates diverse functions, many of which are just now being appreciated. MR that pertain to the central modulation of cardiovascular function and health are addressed herein.Copyright © 2009 S. Karger AG, Basel Historical PerspectiveAddison described patients with adrenal cortical destruction as having 'asthenic' hearts over 150 years ago. A century later deoxycorticosterone became the first effective treatment of Addison disease [1] ; however, it was soon recognized that overzealous replacement led to hypertension and renal damage [2] and that it increased vascular responses to epinephrine and norepinephrine in healthy people [3] . Within a few years aldosterone, the primary mineralocorticoid, was isolated [4] , and primary aldosteronism (Conn's syndrome) was described as associated with refractory hypertension and hypokalemia leading to heart and kidney failure [5] . Notwithstanding early evidence of cardiovascular effects [3,6,7] occurring before the appearance of hypertension, the retention of gested that the inflammation leading to fibrosis and hypertrophy of the heart, vessels and kidneys associated with systemic mineralocorticoid + salt excess were mediated by MR in these tissues independently of significant increases in blood pressure [14][15][16][17] . The assumption that 'end organ' pathology is totally independent of hypertension has been contested [18] . MR are prominently expressed in the macrophages, important components of the inflammatory response that migrate into tissue and produce inflammatory cytokines soon after injury, as well as be...

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Downregulation of brain mineralocorticoid and glucocorticoid receptor by antisense oligodeoxynucleotide treatment fails to alter spatial navigation in rats

Cited by 16 publications

References 38 publications

Stress Induces a Switch of Intracellular Signaling in Sensory Neurons in a Model of Generalized Pain

Stress Induces a Switch of Intracellular Signaling in Sensory Neurons in a Model of Generalized Pain

Expression of Spinal NMDA Receptor and PKCγ after Chronic Morphine Is Regulated by Spinal Glucocorticoid Receptor

Central Mineralocorticoid Receptors and Cardiovascular Disease

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