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      Electrical peripheral nerve stimulation relieves bone cancer pain by inducing Arc protein expression in the spinal cord dorsal horn

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          Abstract

          Objective

          The analgesic effect on chronic pain of peripheral nerve stimulation (PNS) has been proven, but its underlying mechanism remains unknown. Therefore, this study aimed to assess the analgesic effect of PNS on bone cancer pain in a rat model and to explore the underlying mechanism.

          Materials and methods

          PNS on sciatic nerves with bipolar electrode was performed in both naïve and bone cancer pain model rats. Then, the protein levels of activity-regulated cytoskeleton-associated protein (Arc), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type glutamate receptor 1 (GluA1), and phosphate N-methyl- d-aspartic acid-type glutamate receptor subunit 2B (pGluNR2B) in spinal cord were evaluated by immunohistochemistry and Western blotting. Thermal paw withdraw latency and mechanical paw withdraw threshold were used to estimate the analgesic effect of PNS on bone cancer pain. Intrathecal administration of Arc shRNA was used to inhibit Arc expression in the spinal cord.

          Results

          PNS at 60 and 120 Hz for 20 min overtly induced Arc expression in the spinal cord, increased thermal pain thresholds in naïve rats, and relieved bone cancer pain; meanwhile, 10 Hz PNS did not achieve those results. In addition, PNS at 60 and 120 Hz also reduced the expression of GluA1, but not pGluNR2B, in the spinal cord. Finally, the anti-nociceptive effect and GluA1 downregulation induced by PNS were inhibited by intrathecal administration of Arc shRNA.

          Conclusion

          PNS (60 Hz, 0.3 mA) can relieve bone-cancer-induced allodynia and hyperalgesia by upregulating Arc protein expression and then by decreasing GluA1 transcription in the spinal cord dorsal horn.

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          Most cited references 29

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          Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking.

          Arc/Arg3.1 is an immediate-early gene whose mRNA is rapidly transcribed and targeted to dendrites of neurons as they engage in information processing and storage. Moreover, Arc/Arg3.1 is known to be required for durable forms of synaptic plasticity and learning. Despite these intriguing links to plasticity, Arc/Arg3.1's molecular function remains enigmatic. Here, we demonstrate that Arc/Arg3.1 protein interacts with dynamin and specific isoforms of endophilin to enhance receptor endocytosis. Arc/Arg3.1 selectively modulates trafficking of AMPA-type glutamate receptors (AMPARs) in neurons by accelerating endocytosis and reducing surface expression. The Arc/Arg3.1-endocytosis pathway appears to regulate basal AMPAR levels since Arc/Arg3.1 KO neurons exhibit markedly reduced endocytosis and increased steady-state surface levels. These findings reveal a novel molecular pathway that is regulated by Arc/Arg3.1 and likely contributes to late-phase synaptic plasticity and memory consolidation.
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            Increased expression of the immediate-early gene arc/arg3.1 reduces AMPA receptor-mediated synaptic transmission.

            Arc/Arg3.1 is an immediate-early gene whose expression levels are increased by strong synaptic activation, including synapse-strengthening activity patterns. Arc/Arg3.1 mRNA is transported to activated dendritic regions, conferring the distribution of Arc/Arg3.1 protein both temporal correlation with the inducing stimulus and spatial specificity. Here, we investigate the effect of increased Arc/Arg3.1 levels on synaptic transmission. Surprisingly, Arc/Arg3.1 reduces the amplitude of synaptic currents mediated by AMPA-type glutamate receptors (AMPARs). This effect is prevented by RNAi knockdown of Arc/Arg3.1, by deleting a region of Arc/Arg3.1 known to interact with endophilin 3 or by blocking clathrin-coated endocytosis of AMPARs. In the hippocampal slice, Arc/Arg3.1 results in removal of AMPARs composed of GluR2 and GluR3 subunits (GluR2/3). Finally, Arc/Arg3.1 expression occludes NMDAR-dependent long-term depression. Our results demonstrate that Arc/Arg3.1 reduces the number of GluR2/3 receptors leading to a decrease in AMPAR-mediated synaptic currents, consistent with a role in the homeostatic regulation of synaptic strength.
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              Arc in the nucleus regulates PML dependent GluA1 transcription and homeostatic plasticity

              The activity-regulated cytoskeletal protein Arc/Arg3.1 is required for long-term memory formation and synaptic plasticity. Arc expression is robustly induced by activity, and Arc protein localizes both to active synapses and the nucleus. While its synaptic function has been examined, it is not clear why or how Arc is localized to the nucleus. We found that murine Arc nuclear expression is regulated by synaptic activity in vivo and in vitro. We identified distinct regions of Arc that control its localization, including a nuclear localization signal, a nuclear retention domain, and a nuclear export signal. Arc localization to the nucleus promotes an activity-induced increase in promyelocytic leukemia nuclear bodies, which decreases GluA1 transcription and synaptic strength. Finally, we show that Arc nuclear localization regulates homeostatic plasticity. Thus, Arc mediates the homeostatic response to increased activity by translocating to the nucleus, increasing promyelocytic leukemia levels, and decreasing GluA1 transcription, ultimately downscaling synaptic strength.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2018
                21 March 2018
                : 11
                : 599-609
                Affiliations
                [1 ]Department of Orthopedic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
                [2 ]Department of Orthopedics, Lianyungang Oriental Hospital, Lianyungang, Jiangsu, China
                [3 ]Department of Orthopedics, Affiliated Lianyungang Oriental Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, China
                [4 ]Center for Clinical Research and Translation Medicine, Lianyungang Oriental Hospital, Lianyungang, Jiangsu, China
                Author notes
                Correspondence: Hui-lin Yang, Department of Orthopaedic Surgery, the First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Suzhou, Jiangsu 215006, China, Email huilinyangsuda@ 123456163.com
                Article
                jpr-11-599
                10.2147/JPR.S149470
                5868598
                © 2018 Sun et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Anesthesiology & Pain management

                bone cancer pain, peripheral nerve stimulation, glua1, arc

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