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  3. A novel dopamine D2 receptor-NR2B protein complex might contribute to morphine use disorders

A novel dopamine D2 receptor-NR2B protein complex might contribute to morphine use disorders

  • Eur J Pharmacol. 2023 Nov 6:176174. doi: 10.1016/j.ejphar.2023.176174.
Axiang Li 1,  Weifen Li 2,  Tahir Ali 3,  Canyu Yang 4,  Zizhen Liu 5,  Ruyan Gao 6,  Kaiwu He 7,  Xin-An Liu 8,  Zuxin Chen 9,  Zhi-Jian Yu 10,  Tao Li 11,  Shupeng Li 12
Affiliations

Affiliations

  • 1 Institute of Forensic Injury, Institute of Forensic Bio-Evidence, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, China. Electronic address: liaxiang5045@stu.xjtu.edu.cn.
  • 2 State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. Electronic address: 2001112065@pku.edu.cn.
  • 3 State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China; Shenzhen Bay Laboratory, Shenzhen, 518055, China. Electronic address: tali@bs.qau.edu.pk.
  • 4 Institute of Forensic Injury, Institute of Forensic Bio-Evidence, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, China. Electronic address: yangcanyu1996@stu.xjtu.edu.cn.
  • 5 State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. Electronic address: ZzLiu@pku.edu.cn.
  • 6 State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. Electronic address: gaoruyan@pku.edu.cn.
  • 7 State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. Electronic address: 1701111197@pku.edu.cn.
  • 8 Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China; University of Chinese Academy of Sciences, Beijing, China. Electronic address: xa.liu@siat.ac.cn.
  • 9 Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China; University of Chinese Academy of Sciences, Beijing, China; Shenzhen Key Laboratory of Drug Addiction, Shenzhen Neher Neural Plasticity Laboratory, The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), China. Electronic address: zx.chen3@siat.ac.cn.
  • 10 Department of Infectious Diseases and Shenzhen Key Laboratory for Endogenous Infections, The 6th Affiliated Hospital of Shenzhen University Health Science Center, No 89, Taoyuan Road, Nanshan District, Shenzhen, 518052, China. Electronic address: yuzhijiansmu@163.com.
  • 11 Institute of Forensic Injury, Institute of Forensic Bio-Evidence, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, China. Electronic address: litao050428@xjtu.edu.cn.
  • 12 State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China; Shenzhen Bay Laboratory, Shenzhen, 518055, China; Campbell Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. Electronic address: lisp@pku.edu.cn.
PMID: 37939993 DOI: 10.1016/j.ejphar.2023.176174
Abstract

Dopamine receptors can form heteromeric interactions with other receptors, including glutamate receptors, and present a novel pharmacological target because it contribute to dopamine-dysregulated brain disorders such as addiction and other motor-related diseases. In addition, dopamine receptors D2 (D2Rs) and glutamate NMDA receptors subtype-NR2B have been implicated in morphine use disorders; however, the molecular mechanism underlying the heteromeric complex of these two receptors in morphine use disorders is unclear. Herein, we focus on interactions between D2R and NR2B in morphine-induced conditioned place preference (CPP) and hyperlocomotion mice models. We found that the D2R-NR2B complex significantly increases in morphine-induced mice models, accompanied by ERK signaling impairment, implying the complex could contribute to the morphine addiction pathophysiological process. Further, we design a brain-penetrant interfering peptide (TAT-D2-KT), which could disrupt interactions of D2R-NR2B and decrease addictive-like behaviors concurrent to ERK signaling improvement. In summary, our data provided the first evidence for a D2R-NMDAR complex formation in morphine use disorders and its underlying mechanism of ERK signaling, which could present a novel therapeutic target with direct implications for morphine acquisition and relapse treatment.

Keywords

D2 receptor; Morphine use disorders; NMDA receptor; Relapse.

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