eIF4E-Dependent Translation Potentially Regulates Apoptosis and BDNF/TrkB Signaling in the Medial Prefrontal Cortex During Morphine-Induced CPP

  • Int J Mol Sci. 2026 Jun 4;27(11):5097. doi: 10.3390/ijms27115097.
Feifei Gao  1  2 ,  Xixi Yang  1  2 ,  Yuyanran Zhang  3 ,  Dongyu Yu  1  2 ,  Jie Chen  1  2 ,  Beilin Hou  1  2 ,  Zhuojin Yang  1  2 ,  Lanjiang Li  4 ,  Danmei Wang  1  2 ,  Shaqin Xie  1  2 ,  Danni Gao  1  2 ,  Xin Liu  1  2 ,  Hongrui Qian  1  2 ,  Yuxiang Zhang  1  2 ,  Chunxia Yan  1  2  5
Affiliations
  • 1. Key Laboratory of Forensic Medicine of National Health Commission, College of Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China.
  • 2. Bio-Evidence Science Academy, Science and Technology Innovation Harbour of Western China, Xi'an Jiaotong University, Xi-Xian New Area Fengxi New City, Xi'an 712000, China.
  • 3. Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an 710004, China.
  • 4. Key Laboratory of Drug Addiction Medicine of National Health Commission, School of Forensic Medicine, Kunming Medical University, Kunming 650504, China.
  • 5. National Narcotics Laboratory Shaanxi Branch, Xi-Xian New Area Fengxi New City, Xi'an 712000, China.
PMID: 42278621 DOI: 10.3390/ijms27115097
Abstract

Morphine addiction is driven in part by persistent reward-associated memory, yet the molecular mechanisms linking translational control to cellular stress responses remain unclear. In the present study, using a mouse morphine-induced conditioned place preference and N2a cell model, we investigated apoptosis-related alterations in the medial prefrontal cortex and the involvement of eIF4E-dependent translational regulation and BDNF/TrkB signaling. Morphine-induced conditioned place preference was associated with an increase in TUNEL-positive cells in the medial prefrontal cortex, accompanied by upregulation of Bax and downregulation of Bcl-2. In N2a cells, morphine induced Apoptosis in a dose-dependent manner. Morphine also increased neuronal eIF4E expression in both mPFC tissue and N2a cells, accompanied by upregulation of BDNF and TrkB. Inhibition of the eIF4E/eIF4G interaction with 4EGI-1 significantly affected morphine-induced CPP formation and altered apoptosis-related markers and BDNF/TrkB expression. Notably, intra-mPFC administration of 4EGI-1 suppressed morphine-induced CPP without affecting anxiety-like behavior, locomotor activity, or general learning and memory performance. These findings suggest that eIF4E-dependent translational regulation is functionally associated with morphine-induced reward memory and Apoptosis, potentially in association with changes in BDNF/TrkB molecular expression. This study offers novel insight into the molecular basis of morphine addiction and highlights a potentially targetable translational regulatory pathway for therapeutic intervention.

Keywords
apoptosis; brain-derived neurotrophic factor; eukaryotic translation initiation factor 4E; medial prefrontal cortex; morphine; reward memory.
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