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A Conantokin Peptide Con-T[M8Q] Inhibits Morphine Dependence with High Potency and Low Side Effects
N-methyl-D-aspartate receptor (NMDAR) antagonists have been found to be effective to inhibit morphine dependence. However, the discovery of the selective antagonist for NMDAR GluN2B with low side-effects still remains challenging. In the present study, we report a selective NMDAR GluN2B antagonist c...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835912/ https://www.ncbi.nlm.nih.gov/pubmed/33478061 http://dx.doi.org/10.3390/md19010044 |
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author | Liu, Zhuguo Yu, Zheng Yu, Shuo Zhu, Cui Dong, Mingxin Mao, Wenxiang Hu, Jie Prorok, Mary Su, Ruibin Dai, Qiuyun |
author_facet | Liu, Zhuguo Yu, Zheng Yu, Shuo Zhu, Cui Dong, Mingxin Mao, Wenxiang Hu, Jie Prorok, Mary Su, Ruibin Dai, Qiuyun |
author_sort | Liu, Zhuguo |
collection | PubMed |
description | N-methyl-D-aspartate receptor (NMDAR) antagonists have been found to be effective to inhibit morphine dependence. However, the discovery of the selective antagonist for NMDAR GluN2B with low side-effects still remains challenging. In the present study, we report a selective NMDAR GluN2B antagonist con-T[M8Q](a conantokin-T variant) that potently inhibits the naloxone-induced jumping and conditioned place preference of morphine-dependent mice at nmol/kg level, 100-fold higher than ifenprodil, a classical NMDAR NR2B antagonist. Con-T[M8Q] displays no significant impacts on coordinated locomotion function, spontaneous locomotor activity, and spatial memory mice motor function at the dose used. Further molecular mechanism experiments demonstrate that con-T[M8Q] effectively inhibited the transcription and expression levels of signaling molecules related to NMDAR NR2B subunit in hippocampus, including NR2B, p-NR2B, CaMKII-α, CaMKII-β, CaMKIV, pERK, and c-fos. The high efficacy and low side effects of con-T[M8Q] make it a good lead compound for the treatment of opiate dependence and for the reduction of morphine usage. |
format | Online Article Text |
id | pubmed-7835912 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-78359122021-01-27 A Conantokin Peptide Con-T[M8Q] Inhibits Morphine Dependence with High Potency and Low Side Effects Liu, Zhuguo Yu, Zheng Yu, Shuo Zhu, Cui Dong, Mingxin Mao, Wenxiang Hu, Jie Prorok, Mary Su, Ruibin Dai, Qiuyun Mar Drugs Article N-methyl-D-aspartate receptor (NMDAR) antagonists have been found to be effective to inhibit morphine dependence. However, the discovery of the selective antagonist for NMDAR GluN2B with low side-effects still remains challenging. In the present study, we report a selective NMDAR GluN2B antagonist con-T[M8Q](a conantokin-T variant) that potently inhibits the naloxone-induced jumping and conditioned place preference of morphine-dependent mice at nmol/kg level, 100-fold higher than ifenprodil, a classical NMDAR NR2B antagonist. Con-T[M8Q] displays no significant impacts on coordinated locomotion function, spontaneous locomotor activity, and spatial memory mice motor function at the dose used. Further molecular mechanism experiments demonstrate that con-T[M8Q] effectively inhibited the transcription and expression levels of signaling molecules related to NMDAR NR2B subunit in hippocampus, including NR2B, p-NR2B, CaMKII-α, CaMKII-β, CaMKIV, pERK, and c-fos. The high efficacy and low side effects of con-T[M8Q] make it a good lead compound for the treatment of opiate dependence and for the reduction of morphine usage. MDPI 2021-01-19 /pmc/articles/PMC7835912/ /pubmed/33478061 http://dx.doi.org/10.3390/md19010044 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Liu, Zhuguo Yu, Zheng Yu, Shuo Zhu, Cui Dong, Mingxin Mao, Wenxiang Hu, Jie Prorok, Mary Su, Ruibin Dai, Qiuyun A Conantokin Peptide Con-T[M8Q] Inhibits Morphine Dependence with High Potency and Low Side Effects |
title | A Conantokin Peptide Con-T[M8Q] Inhibits Morphine Dependence with High Potency and Low Side Effects |
title_full | A Conantokin Peptide Con-T[M8Q] Inhibits Morphine Dependence with High Potency and Low Side Effects |
title_fullStr | A Conantokin Peptide Con-T[M8Q] Inhibits Morphine Dependence with High Potency and Low Side Effects |
title_full_unstemmed | A Conantokin Peptide Con-T[M8Q] Inhibits Morphine Dependence with High Potency and Low Side Effects |
title_short | A Conantokin Peptide Con-T[M8Q] Inhibits Morphine Dependence with High Potency and Low Side Effects |
title_sort | conantokin peptide con-t[m8q] inhibits morphine dependence with high potency and low side effects |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835912/ https://www.ncbi.nlm.nih.gov/pubmed/33478061 http://dx.doi.org/10.3390/md19010044 |
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