期刊
MARINE DRUGS
卷 19, 期 1, 页码 -出版社
MDPI
DOI: 10.3390/md19010044
关键词
conantokin; con-T[M8Q]; NMDA receptor GluN2B subunit; morphine dependence
资金
- National Natural Science Foundation of China [81473192, 81173035]
- National Basic Research Program of China [2010CB529802]
The study reported a selective NMDAR GluN2B antagonist con-T[M8Q] that potently inhibits morphine dependence in mice with low side effects. The compound effectively inhibits the transcription and expression levels of signaling molecules related to NMDAR NR2B subunit in the hippocampus.
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-alpha, CaMKII-beta, 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.
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