Dataset Information

Proteomic Identification of an Upregulated Isoform of Annexin A3 in the Spinal Cords of Rats in a Neuropathic Pain Model.

ABSTRACT: Neuropathic pain (NP) is induced by nerve damage or a disturbance in the peripheral or central nervous systems. Nerve damage causes the activation of sensitizing mechanisms in the peripheral and central nervous systems, which induces transcriptional and post-transcriptional alterations in sensory nerves. However, the underlying mechanisms of NP remain elusive. In the study, Two-dimensional gel electrophoresis (2DGE)-based comparative proteomics identified 38 differential gel spots, and 15 differentially expressed proteins (DEPs) between the sham and the chronic constriction injury (CCI)-induced neuropathic pain rats. Of them, Annexin A3 (ANXA3) was significantly increased after CCI with Western blot analysis and immunofluorescence imaging. A lentivirus delivering ANXA3 shRNA (LV-shANXA3) was administered intrathecally to determine the analgesic effects of ANXA3 on allodynia and hyperalgesia in a CCI-induced neuropathic pain model in rats. Further study showed that LV-shANXA3 reversed the upregulation of ANXA3, alleviated CCI-induced mechanical allodynia and thermal hyperalgesia. The study indicated that ANXA3 may play an important role in neuropathic pain.

SUBMITTER: Zou W

PROVIDER: S-EPMC5591859 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Proteomic Identification of an Upregulated Isoform of Annexin A3 in the Spinal Cords of Rats in a Neuropathic Pain Model.

Zou Wangyuan W Xu Wei W Song Zongbin Z Zhong Tao T Weng Yingqi Y Huang Changsheng C Li Maoyu M Zhang Chuanlei C Zhan Xianquan X Guo Qulian Q

Frontiers in neuroscience 20170905

Neuropathic pain (NP) is induced by nerve damage or a disturbance in the peripheral or central nervous systems. Nerve damage causes the activation of sensitizing mechanisms in the peripheral and central nervous systems, which induces transcriptional and post-transcriptional alterations in sensory nerves. However, the underlying mechanisms of NP remain elusive. In the study, Two-dimensional gel electrophoresis (2DGE)-based comparative proteomics identified 38 differential gel spots, and 15 differ ...[more]

PMID: 28928629

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Project description:BackgroundNeuropathic pain (NP) is a prevalent disease, which badly impairs the life quality of patients. The underlying mechanism of NP is still not fully understood. It has been reported that spinal Annexin A10 (ANXA10) contributes to NP. This study aims at exploring the underlying mechanisms of spinal ANXA10 in regulating NP in rats.MethodsSpinal nerve ligation (SNL) was adopted to establish a NP model in rats. After SNL, paw withdrawal threshold and paw withdrawal latency were recorded to measure pain behaviors, RT-PCR was used to check the change of the expression of spinal ANXA10 mRNA, western blot analysis was used to detect the change of the protein level of ANXA10, nuclear factor kappa B (NF-κB), and maisrix metalloproteinase-9 (MMP-9) in the spinal cord. The levels of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukine-1β (IL-1β), and interleukine-6 (IL-6), were explored by ELISA kits. The effects of both knockdown of spinal ANXA10 and inhibition of NF-κB on pain behaviors and the expression of MMP-9 and proinflammatory cytokines were investigated.ResultsOur present findings highlighted that SNL caused pain hypersensitivity and increased the expression of spinal ANXA10/pNF-κB, TNF-α, IL-1β, and IL-6 both in the early and late phase of NP in rats, while spinal MMP-9 was only slightly increased in the early phase of NP. Knockdown of ANXA10 at the spinal cord level suppressed the SNL-induced hyperalgesia and blocked the activation of NF-κB, TNF-α and IL-1β both in the early and late phase of NP. Spinal ANXA10 knockdown could prevent the upregulation of spinal MMP-9 in the early phase and inhibit IL-6 expression in the late phase of SNL-induced NP.ConclusionsIn conclusion, spinal ANXA10/NF-κB/MMP-9 pathway, along with the activation of proinflammatory cytokines, was involved in the SNL-induced NP. MMP-9 may act as the downstream target of ANXA10/NF-κB pathway in the development rather than the maintenance of NP.

Project description:Neuropathic pain, a debilitating pain condition, is a common consequence of damage to the nervous system. Optimal treatment of neuropathic pain is a major clinical challenge because the underlying mechanisms remain unclear and currently available treatments are frequently ineffective. Emerging lines of evidence indicate that peripheral nerve injury converts resting spinal cord glia into reactive cells that are required for the development and maintenance of neuropathic pain. However, the mechanisms underlying reactive astrogliosis after nerve injury are largely unknown. In the present study, we investigated cell proliferation, a critical process in reactive astrogliosis, and determined the temporally restricted proliferation of dorsal horn astrocytes in rats with spinal nerve injury, a well-known model of neuropathic pain. We found that nerve injury-induced astrocyte proliferation requires the Janus kinase-signal transducers and activators of transcription 3 signalling pathway. Nerve injury induced a marked signal transducers and activators of transcription 3 nuclear translocation, a primary index of signal transducers and activators of transcription 3 activation, in dorsal horn astrocytes. Intrathecally administering inhibitors of Janus kinase-signal transducers and activators of transcription 3 signalling to rats with nerve injury reduced the number of proliferating dorsal horn astrocytes and produced a recovery from established tactile allodynia, a cardinal symptom of neuropathic pain that is characterized by pain hypersensitivity evoked by innocuous stimuli. Moreover, recovery from tactile allodynia was also produced by direct suppression of dividing astrocytes by intrathecal administration of the cell cycle inhibitor flavopiridol to nerve-injured rats. Together, these results imply that the Janus kinase-signal transducers and activators of transcription 3 signalling pathway are critical transducers of astrocyte proliferation and maintenance of tactile allodynia and may be a therapeutic target for neuropathic pain.

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.

Dataset Information

Proteomic Identification of an Upregulated Isoform of Annexin A3 in the Spinal Cords of Rats in a Neuropathic Pain Model.

Publications

Proteomic Identification of an Upregulated Isoform of Annexin A3 in the Spinal Cords of Rats in a Neuropathic Pain Model.

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