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On the possible role of ERK, p38 and CaMKII in the regulation of CGRP expression in morphine-tolerant rats.

ABSTRACT: The neuropeptide, calcitonin gene-related peptide (CGRP) has been proposed to be a regulator of the development of morphine analgesic tolerance and thereby could be a target to reduce the induction of this phenomenon under clinical conditions. However, the mechanisms of CGRP regulation are unclear. We investigated here the possible role of the extracellular signal-regulated protein kinase (ERK), p38 and calcium/calmodulin-dependent protein kinase II (CaMKII) in CGRP regulation following chronic morphine treatment.A 7-day treatment with morphine (15 ?g/day) led to an increase in CGRP contents in the spinal cord dorsal horn (SCDH) and dorsal root ganglion (DRG) and this effect was prevented by the inhibition of the ERK, p38 or CaMKII pathway. The phosphorylation/activation of ERK, p38 and CaMKII was enhanced in the SCDH following chronic morphine while in DRG only the phosphorylation of CaMKII was increased. Moreover, our chronic morphine treatment up-regulated neuronal nitric oxide synthase (nNOS) levels in the SCDH, an effect blocked by the inhibition of the ERK, p38 or CaMKII pathway. The blockade of nNOS activity also suppressed chronic morphine-induced CGRP increases in the DRG and SCDH. Double immunofluorescence studies revealed that nNOS and CaMKII are co-localized in the SCDH and that CaMKII is activated in CGRP-expressing DRG neurons.The activation of spinal ERK, p38 and CaMKII, alongside nNOS, is involved in chronic morphine-induced CGRP up-regulation in both the DRG and SCDH. Moreover, the stimulation of CaMKII in the DRG likely directly regulates the expression of CGRP associated with morphine analgesic tolerance.

SUBMITTER: Wang Z

PROVIDER: S-EPMC3190348 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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On the possible role of ERK, p38 and CaMKII in the regulation of CGRP expression in morphine-tolerant rats.

Wang Zhiyong Z Chabot Jean-Guy JG Quirion Remi R

Molecular pain 20110921

<h4>Background</h4>The neuropeptide, calcitonin gene-related peptide (CGRP) has been proposed to be a regulator of the development of morphine analgesic tolerance and thereby could be a target to reduce the induction of this phenomenon under clinical conditions. However, the mechanisms of CGRP regulation are unclear. We investigated here the possible role of the extracellular signal-regulated protein kinase (ERK), p38 and calcium/calmodulin-dependent protein kinase II (CaMKII) in CGRP regulation ...[more]

PMID: 21933441

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Project description:Morphine tolerance is a challenging clinical problem that limits the use of morphine in pain treatment, but the mechanisms of morphine tolerance remain unclear. Recent research indicates that long noncoding RNAs (lncRNAs) might be a novel and promising target in the pathogeneses of diseases. Therefore, we hypothesized that lncRNAs might play a role in the development of morphine tolerance. Male Sprague-Dawley rats were intrathecally injected with 10 ?g morphine twice daily for 7 consecutive days. The animals were then sacrificed for lncRNA microarray tests, and the results were validated by RT-qPCR. Next, functional predictions for the differentially expressed mRNAs (DEmRNAs) were made with the Gene Ontology/Kyoto Encyclopedia of Genes and Genomes (GO/KEGG), and predictions for the differentially expressed lncRNAs (DElncRNAs) were made based on competitive endogenous RNA (ceRNA) analyses. The rats successfully developed morphine tolerance. LncRNA microarray analysis revealed that, according to the criteria of a log2 (fold change)?>?1.5 and a P-value <?0.05, 136 lncRNAs and 278 mRNAs were differentially expressed in the morphine tolerance group (MT) compared with the normal saline group (NS). The functions of the DEmRNAs likely involve in the processes of the ion channel transport, pain transmission and immune response. The ceRNA analysis indicated that several possible interacting networks existed, including (MRAK150340, MRAK161211)/miR-219b/Tollip.Further annotations of the potential target mRNAs of the miRNAs according to the gene database suggested that the possible functions of these mRNAs primarily involved the regulation of ubiquitylation, G protein-linked receptors, and Toll-like receptors, which play roles in the development of morphine tolerance. Our findings revealed the profiles of differentially expressed lncRNAs in morphine tolerance conditions, and among these lncRNAs, some DElncRNAs might be new therapeutic targets for morphine tolerance.

Project description:Vascular dementia (VaD) is a common cause of cognitive decline and dementia of vascular origin, but the precise pathological mechanisms are unknown, and so effective clinical treatments have not been established. Tilianin, the principal active compound of total flavonoid extract from Dracocephalum moldavica L., is a candidate therapy for cardio-cerebrovascular diseases in China. However, its potential in the treatment of VaD is unclear. The present study is aimed at investigating the protective effects of tilianin on VaD and exploring the underlying mechanism of the action. A model of VaD was established by permanent 2-vessel occlusion (2VO) in rats. Human neurons (hNCs) differentiated from human-induced pluripotent stem cells were used to establish an oxygen-glucose deprivation (OGD) model. The therapeutic effects and potential mechanisms of tilianin were identified using behavioral tests, histochemistry, and multiple molecular biology techniques such as Western blot analysis and gene silencing. The results demonstrated that tilianin modified spatial cognitive impairment, neurodegeneration, oxidation, and apoptosis in rats with VaD and protected hNCs against OGD by increasing cell viability and decreasing apoptosis rates. A study of the mechanism indicated that tilianin restored p-CaMKII/ERK1/2/CREB signaling in the hippocampus, maintaining hippocampus-independent memory. In addition, tilianin inhibited an ox-CaMKII/p38 MAPK/JNK/NF-κB associated inflammatory response caused by cerebral oxidative stress imbalance in rats with VaD. Furthermore, specific CaMKIIα siRNA action revealed that tilianin-exerted neuroprotection involved increase of neuronal viability, inhibition of apoptosis, and suppression of inflammation, which was dependent on CaMKIIα. In conclusion, the results suggested the neuroprotective effect of tilianin in VaD and the potential mechanism associated with dysfunction in the regulation of p-CaMKII-mediated long-term memory and oxidation and inflammation involved with ox-CaMKII, which may lay the foundation for clinical trials of tilianin for the treatment of VaD in the future.

Dataset Information

On the possible role of ERK, p38 and CaMKII in the regulation of CGRP expression in morphine-tolerant rats.

Publications

On the possible role of ERK, p38 and CaMKII in the regulation of CGRP expression in morphine-tolerant rats.

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