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Summary: Normally, opioids function in a receptor-dependent manner. They bind to opioid receptors, activate or inhibit receptor activation, and subsequently modulate downstream signal transduction. However, the complex functions of opioids and the low expression of opioid receptors and their endogenous peptide agonists in neural stem cells (NSCs) suggest that some opioids may also modulate NSCs via a receptor-independent pathway. In the current study, two opioids, morphine and naloxone, are demonstrated to facilitate NSC proliferation via a receptor-independent and ten-eleven translocation methylcytosine dioxygenase 1 (TET1)-dependent pathway. Morphine and naloxone penetrate cell membrane, bind to TET1 protein via three key residues (1,880–1,882), and subsequently result in facilitated proliferation of NSCs. In addition, the two opioids also inhibit the DNA demethylation ability of TET1. In summary, the current results connect opioids and DNA demethylation directly at least in NSCs and extend our understanding on both opioids and NSCs. : Liang et al. demonstrate a receptor-independent and Tet1-dependent pathway used by opioids naloxone and morphine to facilitate the proliferation of NSCs. The binding of naloxone and morphine to TET1 suggests that DNA methylation should be considered when studying the tolerance- and addiction-induced opioids. Keywords: neural stem cells, naloxone, morphine, Tet1, receptor-independent, proliferation