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Study Shows Opioids Regulate Neural Stem Cells Differentiation via Receptor-independent Pathway


A new research by scientists from Guangzhou Institute of Biomedicine and Health (GIBH), Chinese Academy of Sciences revealed the role of the opioid receptor-independent pathway in the regulation of neural stem cells (NSCs) differentiation by the opioid receptor antagonist naloxone. 

The study was carried out by research group of ZHENG Hui from GIBH and Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL). Results of the study was published in the FASEB Journal on March 10th, entitled “Naloxone Regulates the Differentiation of Neural Stem Cells via a Receptor-independent Pathway” (https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.201902873R). 

Numerous studies have shown that opioids can regulate the direction of NSCs differentiation and affect adult neurogenesis and the ability to learn and remember. However, whether the effects of opioids on NSCs differentiation depend entirely on opioid receptors remains a question. 

The differentiation of NSCs refers to the process by which neural stem cells produce neurons, astrocytes, and oligodendrocytes through asymmetric division.  

ZHENG’s team took the opioid antagonist naloxone as the representative to study the regulation of opioids on the differentiation of NSCs. Naloxone promotes the differentiation of NSCs toward neurons by entering the cell, with very low expression of opioid receptors and their endogenous ligands, their study found. 

The naloxone analog naloxone methiodide, which loses the ability to penetrate the cell membrane, did not affect the differentiation of NSCs. 

Further research showed that naloxone treatment changed the DNA demethylation ability of TET1 and genomic methylation level of cells. Subsequently, the researchers used Tet1 knockout cells to prove that the regulation of naloxone on NSC differentiation depends on Tet1, and has nothing to do with Tet2 or Tet3 of the same family. 

The research group also confirmed that other opioids can also regulate NSCs differentiation through opioid receptor-independent pathway. “Adding morphine in the early stage of NSCs differentiation can also promote the differentiation of NSCs into neurons,” said ZHENG. 

During the late stage of neural differentiation when the expression level of opioid receptors gradually increased, morphine promoted the differentiation toward astrocytes through opioid receptor pathway. 

This study shows the role of opioid receptor-independent pathway in the regulation of opioids on NSC differentiation, and provides new insights into the regulatory effects of opioids on the neural system. 

This work was supported by the Strategic Priority Research Program of CAS, the Key Research Program of Frontier Sciences, CAS, the National Natural Science Foundation of China, and the Key Research & Development Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory, and the Science and Technology Planning Project of Guangdong Province. 


Study Shows Opioids Regulate Neural Stem Cells Differentiation via Receptor-independent Pathway