A Conantokin Peptide Con-T[M8Q] Inhibits Morphine Dependence with High Potency and Low Side Effects |
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| Authors: | Zhuguo Liu Zheng Yu Shuo Yu Cui Zhu Mingxin Dong Wenxiang Mao Jie Hu Mary Prorok Ruibin Su Qiuyun Dai |
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| Affiliation: | 1.Beijing Institute of Biotechnology, Beijing 100071, China; (Z.L.); (Z.Y.); (S.Y.); (C.Z.); (M.D.); (W.M.); (J.H.);2.Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA;3.Beijing Institute of Toxicology and Pharmacology, Beijing 100850, China |
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| Abstract: | 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. |
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| Keywords: | conantokin con-T[M8Q] NMDA receptor GluN2B subunit morphine dependence |
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