Cargando…
Differential regulation of GSK-3β in spinal dorsal horn and in hippocampus mediated by interleukin-1beta contributes to pain hypersensitivity and memory deficits following peripheral nerve injury
Accumulating evidence shows that inhibition of glycogen synthase kinase-3beta (GSK-3β) ameliorates cognitive impairments caused by a diverse array of diseases. Our previous work showed that spared nerve injury (SNI) that induces neuropathic pain causes short-term memory deficits. Here, we reported t...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378430/ https://www.ncbi.nlm.nih.gov/pubmed/30632435 http://dx.doi.org/10.1177/1744806919826789 |
_version_ | 1783395926626271232 |
---|---|
author | Mai, Chun-Lin Wei, Xiao Gui, Wen-Shan Xu, Ya-Nan Zhang, Jun Lin, Zhen-Jia Tan, Zhi Meng, Ying-Tong Li, Yong-Yong Zhou, Li-Jun Liu, Xian-Guo |
author_facet | Mai, Chun-Lin Wei, Xiao Gui, Wen-Shan Xu, Ya-Nan Zhang, Jun Lin, Zhen-Jia Tan, Zhi Meng, Ying-Tong Li, Yong-Yong Zhou, Li-Jun Liu, Xian-Guo |
author_sort | Mai, Chun-Lin |
collection | PubMed |
description | Accumulating evidence shows that inhibition of glycogen synthase kinase-3beta (GSK-3β) ameliorates cognitive impairments caused by a diverse array of diseases. Our previous work showed that spared nerve injury (SNI) that induces neuropathic pain causes short-term memory deficits. Here, we reported that GSK-3β activity was enhanced in hippocampus and reduced in spinal dorsal horn following SNI, and the changes persisted for at least 45 days. Repetitive applications of selective GSK-3β inhibitors (SB216763, 5 mg/kg, intraperitoneally, three times or AR-A014418, 400 ng/kg, intrathecally, seven times) prevented short-term memory deficits but did not affect neuropathic pain induced by SNI. Surprisingly, we found that the repetitive SB216763 or AR-A014418 induced a persistent pain hypersensitivity in sham animals. Mechanistically, both β-catenin and brain-derived neurotrophic factor (BDNF) were upregulated in spinal dorsal horn but downregulated in hippocampus following SNI. Injections of SB216763 prevented the BDNF downregulation in hippocampus but enhanced its upregulation in spinal dorsal horn in SNI rats. In sham rats, SB216763 upregulated both β-catenin and BDNF in spinal dorsal horn but affect neither of them in hippocampus. Finally, intravenous injection of interleukin-1beta that induces pain hypersensitivity and memory deficits mimicked the SNI-induced the differential regulation of GSK-3β/β-catenin/BDNF in spinal dorsal horn and in hippocampus. Accordingly, the prolonged opposite changes of GSK-3β activity in hippocampus and in spinal dorsal horn induced by SNI may contribute to memory deficits and neuropathic pain by differential regulation of BDNF in the two regions. GSK-3β inhibitors that treat cognitive disorders may result in a long-lasting pain hypersensitivity. |
format | Online Article Text |
id | pubmed-6378430 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-63784302019-02-22 Differential regulation of GSK-3β in spinal dorsal horn and in hippocampus mediated by interleukin-1beta contributes to pain hypersensitivity and memory deficits following peripheral nerve injury Mai, Chun-Lin Wei, Xiao Gui, Wen-Shan Xu, Ya-Nan Zhang, Jun Lin, Zhen-Jia Tan, Zhi Meng, Ying-Tong Li, Yong-Yong Zhou, Li-Jun Liu, Xian-Guo Mol Pain Research Article Accumulating evidence shows that inhibition of glycogen synthase kinase-3beta (GSK-3β) ameliorates cognitive impairments caused by a diverse array of diseases. Our previous work showed that spared nerve injury (SNI) that induces neuropathic pain causes short-term memory deficits. Here, we reported that GSK-3β activity was enhanced in hippocampus and reduced in spinal dorsal horn following SNI, and the changes persisted for at least 45 days. Repetitive applications of selective GSK-3β inhibitors (SB216763, 5 mg/kg, intraperitoneally, three times or AR-A014418, 400 ng/kg, intrathecally, seven times) prevented short-term memory deficits but did not affect neuropathic pain induced by SNI. Surprisingly, we found that the repetitive SB216763 or AR-A014418 induced a persistent pain hypersensitivity in sham animals. Mechanistically, both β-catenin and brain-derived neurotrophic factor (BDNF) were upregulated in spinal dorsal horn but downregulated in hippocampus following SNI. Injections of SB216763 prevented the BDNF downregulation in hippocampus but enhanced its upregulation in spinal dorsal horn in SNI rats. In sham rats, SB216763 upregulated both β-catenin and BDNF in spinal dorsal horn but affect neither of them in hippocampus. Finally, intravenous injection of interleukin-1beta that induces pain hypersensitivity and memory deficits mimicked the SNI-induced the differential regulation of GSK-3β/β-catenin/BDNF in spinal dorsal horn and in hippocampus. Accordingly, the prolonged opposite changes of GSK-3β activity in hippocampus and in spinal dorsal horn induced by SNI may contribute to memory deficits and neuropathic pain by differential regulation of BDNF in the two regions. GSK-3β inhibitors that treat cognitive disorders may result in a long-lasting pain hypersensitivity. SAGE Publications 2019-02-08 /pmc/articles/PMC6378430/ /pubmed/30632435 http://dx.doi.org/10.1177/1744806919826789 Text en © The Author(s) 2019 http://creativecommons.org/licenses/by-nc/4.0/ Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Research Article Mai, Chun-Lin Wei, Xiao Gui, Wen-Shan Xu, Ya-Nan Zhang, Jun Lin, Zhen-Jia Tan, Zhi Meng, Ying-Tong Li, Yong-Yong Zhou, Li-Jun Liu, Xian-Guo Differential regulation of GSK-3β in spinal dorsal horn and in hippocampus mediated by interleukin-1beta contributes to pain hypersensitivity and memory deficits following peripheral nerve injury |
title | Differential regulation of GSK-3β in spinal dorsal horn and in hippocampus mediated by interleukin-1beta contributes to pain hypersensitivity and memory deficits following peripheral nerve injury |
title_full | Differential regulation of GSK-3β in spinal dorsal horn and in hippocampus mediated by interleukin-1beta contributes to pain hypersensitivity and memory deficits following peripheral nerve injury |
title_fullStr | Differential regulation of GSK-3β in spinal dorsal horn and in hippocampus mediated by interleukin-1beta contributes to pain hypersensitivity and memory deficits following peripheral nerve injury |
title_full_unstemmed | Differential regulation of GSK-3β in spinal dorsal horn and in hippocampus mediated by interleukin-1beta contributes to pain hypersensitivity and memory deficits following peripheral nerve injury |
title_short | Differential regulation of GSK-3β in spinal dorsal horn and in hippocampus mediated by interleukin-1beta contributes to pain hypersensitivity and memory deficits following peripheral nerve injury |
title_sort | differential regulation of gsk-3β in spinal dorsal horn and in hippocampus mediated by interleukin-1beta contributes to pain hypersensitivity and memory deficits following peripheral nerve injury |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378430/ https://www.ncbi.nlm.nih.gov/pubmed/30632435 http://dx.doi.org/10.1177/1744806919826789 |
work_keys_str_mv | AT maichunlin differentialregulationofgsk3binspinaldorsalhornandinhippocampusmediatedbyinterleukin1betacontributestopainhypersensitivityandmemorydeficitsfollowingperipheralnerveinjury AT weixiao differentialregulationofgsk3binspinaldorsalhornandinhippocampusmediatedbyinterleukin1betacontributestopainhypersensitivityandmemorydeficitsfollowingperipheralnerveinjury AT guiwenshan differentialregulationofgsk3binspinaldorsalhornandinhippocampusmediatedbyinterleukin1betacontributestopainhypersensitivityandmemorydeficitsfollowingperipheralnerveinjury AT xuyanan differentialregulationofgsk3binspinaldorsalhornandinhippocampusmediatedbyinterleukin1betacontributestopainhypersensitivityandmemorydeficitsfollowingperipheralnerveinjury AT zhangjun differentialregulationofgsk3binspinaldorsalhornandinhippocampusmediatedbyinterleukin1betacontributestopainhypersensitivityandmemorydeficitsfollowingperipheralnerveinjury AT linzhenjia differentialregulationofgsk3binspinaldorsalhornandinhippocampusmediatedbyinterleukin1betacontributestopainhypersensitivityandmemorydeficitsfollowingperipheralnerveinjury AT tanzhi differentialregulationofgsk3binspinaldorsalhornandinhippocampusmediatedbyinterleukin1betacontributestopainhypersensitivityandmemorydeficitsfollowingperipheralnerveinjury AT mengyingtong differentialregulationofgsk3binspinaldorsalhornandinhippocampusmediatedbyinterleukin1betacontributestopainhypersensitivityandmemorydeficitsfollowingperipheralnerveinjury AT liyongyong differentialregulationofgsk3binspinaldorsalhornandinhippocampusmediatedbyinterleukin1betacontributestopainhypersensitivityandmemorydeficitsfollowingperipheralnerveinjury AT zhoulijun differentialregulationofgsk3binspinaldorsalhornandinhippocampusmediatedbyinterleukin1betacontributestopainhypersensitivityandmemorydeficitsfollowingperipheralnerveinjury AT liuxianguo differentialregulationofgsk3binspinaldorsalhornandinhippocampusmediatedbyinterleukin1betacontributestopainhypersensitivityandmemorydeficitsfollowingperipheralnerveinjury |