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Up-regulation of anterior cingulate cortex NR2B receptors contributes to visceral pain responses in rats.

ABSTRACT: Electrophysiologic and behavioral studies have shown that increased N-methyl-D-aspartate (NMDA)-receptor activation of anterior cingulate cortex (ACC) neurons has a critical role in modulating visceral pain responses in viscerally hypersensitive (VH) rats. This study aimed to identify the NMDA receptor subtypes in perigenual ACC (pACC) neurons involved in the facilitation of visceral nociception.We performed in vivo electrophysiologic recordings of pACC neurons and examined the visceromotor response (VMR) to colorectal distention (CRD) in normal and VH rats induced by colonic anaphylaxis. The NR2A-subtype-receptor antagonist [(R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid (NVP-AAM077) and the NR2B-receptor-antagonist Ro25-6981 were microinjected into the pACC. To down-regulate NR2B-receptor gene expression, an NR2B-specific small interfering RNA (siRNA) and a plasmid (pEGFP-N1) that expressed the green fluorescent protein were administered into ACC neurons by electroporation.Reverse microdialysis of NVP-AAM077 had no effect on basal and CRD-induced ACC neuronal firing in VH and control groups. In VH rats, Ro25-6981 (500 micromol/L) inhibited ACC neuronal firing, evoked by 30 and 50 mm Hg CRD, by 98% and 52%, respectively. NVP-AAM077 did not affect the VMR in either group. Ro25-6981 significantly suppressed the VMR in VH but not normal rats. Immunoblot analysis showed increased NR2B-receptor expression in the pACC of VH rats. NR2B siRNA-treated VH rats showed a significant reduction in the VMR, compared with controls.The NR2B subunit of the NMDA receptor has a critical role in the modulation of ACC sensitization and visceral pain responses in VH rats.

SUBMITTER: Fan J

PROVIDER: S-EPMC2677121 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Up-regulation of anterior cingulate cortex NR2B receptors contributes to visceral pain responses in rats.

Fan Jing J Wu Xiaoyin X Cao Zhijun Z Chen Shengliang S Owyang Chung C Li Ying Y

Gastroenterology 20090206 5

<h4>Background & aims</h4>Electrophysiologic and behavioral studies have shown that increased N-methyl-D-aspartate (NMDA)-receptor activation of anterior cingulate cortex (ACC) neurons has a critical role in modulating visceral pain responses in viscerally hypersensitive (VH) rats. This study aimed to identify the NMDA receptor subtypes in perigenual ACC (pACC) neurons involved in the facilitation of visceral nociception.<h4>Methods</h4>We performed in vivo electrophysiologic recordings of pACC ...[more]

PMID: 19208366

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Project description:BackgroundNeuropathic pain (NP) takes a heavy toll on individual life quality, yet gaps in its molecular characterization persist and effective therapy is lacking. This study aimed to provide comprehensive knowledge by combining transcriptomic and proteomic data of molecular correlates of NP in the anterior cingulate cortex (ACC), a cortical hub responsible for affective pain processing.MethodsThe NP model was established by spared nerve injury (SNI) in Sprague-Dawley rats. RNA sequencing and proteomic data from the ACC tissue isolated from sham and SNI rats 2 weeks after surgery were integrated to compare their gene and protein expression profiles. Bioinformatic analyses were performed to figure out the functions and signaling pathways of the differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) enriched in.ResultsTranscriptomic analysis identified a total of 788 DEGs (with 49 genes upregulated) after SNI surgery, while proteomic analysis found 222 DEPs (with 89 proteins upregulated). While Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of the DEGs suggested that most of the altered genes were involved in synaptic transmission and plasticity, bioinformatics analysis of the DEPs revealed novel critical pathways associated with autophagy, mitophagy, and peroxisome. Notably, we noticed functionally important NP-related changes in the protein that occurred in the absence of corresponding changes at the level of transcription. Venn diagram analysis of the transcriptomic and proteomic data identified 10 overlapping targets, among which only three genes (XK-related protein 4, NIPA-like domain-containing 3, and homeodomain-interacting protein kinase 3) showed concordance in the directions of change and strong correlations between mRNA and protein levels.ConclusionThe present study identified novel pathways in the ACC in addition to confirming previously reported mechanisms for NP etiology, and provided novel mechanistic insights for future research on NP treatment. These findings also imply that mRNA profiling alone fails to provide a complete landscape of molecular pain in the ACC. Therefore, explorations of changes at the level of protein are necessary to understand NP processes that are not transcriptionally modulated.

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Up-regulation of anterior cingulate cortex NR2B receptors contributes to visceral pain responses in rats.

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Up-regulation of anterior cingulate cortex NR2B receptors contributes to visceral pain responses in rats.

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