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Altered glial glutamate transporter expression in descending circuitry and the emergence of pain chronicity

BACKGROUND: The glutamate type 1 transporter (GLT1) plays a major role in glutamate homeostasis in the brain. Although alterations of GLT1 activity have been linked to persistent pain, the significance of these changes is poorly understood. Focusing on the rostral ventromedial medulla, a key site in...

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Autores principales: Guo, Wei, Imai, Satoshi, Zou, Shiping, Yang, Jiale, Watanabe, Mineo, Wang, Jing, Dubner, Ronald, Wei, Feng, Ren, Ke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348548/
https://www.ncbi.nlm.nih.gov/pubmed/30799685
http://dx.doi.org/10.1177/1744806918825044
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author Guo, Wei
Imai, Satoshi
Zou, Shiping
Yang, Jiale
Watanabe, Mineo
Wang, Jing
Dubner, Ronald
Wei, Feng
Ren, Ke
author_facet Guo, Wei
Imai, Satoshi
Zou, Shiping
Yang, Jiale
Watanabe, Mineo
Wang, Jing
Dubner, Ronald
Wei, Feng
Ren, Ke
author_sort Guo, Wei
collection PubMed
description BACKGROUND: The glutamate type 1 transporter (GLT1) plays a major role in glutamate homeostasis in the brain. Although alterations of GLT1 activity have been linked to persistent pain, the significance of these changes is poorly understood. Focusing on the rostral ventromedial medulla, a key site in pain modulation, we examined the expression and function of GLT1 and related transcription factor kappa B-motif binding phosphoprotein (KBBP) in rats after adjuvant-induced hind paw inflammation. RESULTS: After inflammation, GLT1 and KBBP showed an early upregulation and gradual transition to downregulation that lasted throughout the eight-week observation period. Nitration of GLT1 was reduced at 30 min and increased at eight weeks after inflammation, suggesting an initial increase and later decrease in transporter activity. Mechanical hyperalgesia and paw edema exhibited an initial developing phase with peak hyperalgesia at 4 to 24 h, a subsequent attenuating phase, followed by a late persistent phase that lasted for months. The downregulation of GLT1 occurred at a time when hyperalgesia transitioned into the persistent phase. In the rostral ventromedial medulla, pharmacological block with dihydrokainic acid and RNAi of GLT1 and KBBP increased nociception and overexpression of GLT1 reversed persistent hyperalgesia. Further, the initial upregulation of GLT1 and KBBP was blocked by local anesthetic block, and pretreatment with dihydrokainic acid facilitated the development of hyperalgesia. CONCLUSIONS: These results suggest that the initial increased GLT1 activity depends on injury input and serves to dampen the development of hyperalgesia. However, later downregulation of GLT1 fosters the net descending facilitation as injury persists, leading to the emergence of persistent pain.
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spelling pubmed-63485482019-02-04 Altered glial glutamate transporter expression in descending circuitry and the emergence of pain chronicity Guo, Wei Imai, Satoshi Zou, Shiping Yang, Jiale Watanabe, Mineo Wang, Jing Dubner, Ronald Wei, Feng Ren, Ke Mol Pain Research Article BACKGROUND: The glutamate type 1 transporter (GLT1) plays a major role in glutamate homeostasis in the brain. Although alterations of GLT1 activity have been linked to persistent pain, the significance of these changes is poorly understood. Focusing on the rostral ventromedial medulla, a key site in pain modulation, we examined the expression and function of GLT1 and related transcription factor kappa B-motif binding phosphoprotein (KBBP) in rats after adjuvant-induced hind paw inflammation. RESULTS: After inflammation, GLT1 and KBBP showed an early upregulation and gradual transition to downregulation that lasted throughout the eight-week observation period. Nitration of GLT1 was reduced at 30 min and increased at eight weeks after inflammation, suggesting an initial increase and later decrease in transporter activity. Mechanical hyperalgesia and paw edema exhibited an initial developing phase with peak hyperalgesia at 4 to 24 h, a subsequent attenuating phase, followed by a late persistent phase that lasted for months. The downregulation of GLT1 occurred at a time when hyperalgesia transitioned into the persistent phase. In the rostral ventromedial medulla, pharmacological block with dihydrokainic acid and RNAi of GLT1 and KBBP increased nociception and overexpression of GLT1 reversed persistent hyperalgesia. Further, the initial upregulation of GLT1 and KBBP was blocked by local anesthetic block, and pretreatment with dihydrokainic acid facilitated the development of hyperalgesia. CONCLUSIONS: These results suggest that the initial increased GLT1 activity depends on injury input and serves to dampen the development of hyperalgesia. However, later downregulation of GLT1 fosters the net descending facilitation as injury persists, leading to the emergence of persistent pain. SAGE Publications 2019-01-24 /pmc/articles/PMC6348548/ /pubmed/30799685 http://dx.doi.org/10.1177/1744806918825044 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
Guo, Wei
Imai, Satoshi
Zou, Shiping
Yang, Jiale
Watanabe, Mineo
Wang, Jing
Dubner, Ronald
Wei, Feng
Ren, Ke
Altered glial glutamate transporter expression in descending circuitry and the emergence of pain chronicity
title Altered glial glutamate transporter expression in descending circuitry and the emergence of pain chronicity
title_full Altered glial glutamate transporter expression in descending circuitry and the emergence of pain chronicity
title_fullStr Altered glial glutamate transporter expression in descending circuitry and the emergence of pain chronicity
title_full_unstemmed Altered glial glutamate transporter expression in descending circuitry and the emergence of pain chronicity
title_short Altered glial glutamate transporter expression in descending circuitry and the emergence of pain chronicity
title_sort altered glial glutamate transporter expression in descending circuitry and the emergence of pain chronicity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348548/
https://www.ncbi.nlm.nih.gov/pubmed/30799685
http://dx.doi.org/10.1177/1744806918825044
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