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The mechanism by which addictive drugs such as morphine regulate adult neurogenesis remains elusive. We now demonstrate that morphine can regulate neurogenesis by control of miR‐181a and subsequent hippocampal neural progenitor cell (hNPC) lineages. In the presence of morphine, hNPCs preferentially differentiated into astrocytes, an effect blocked by the specific μ‐opioid receptor antagonist, Cys 2 ‐Tyr 3 ‐Orn 5 ‐Pen 7 ‐amide. This effect was mediated by the Prox1/Notch1 pathway as demonstrated by an increase in Notch1 level in the morphine‐ but not fentanyl‐treated hNPCs and blocked by overexpression of Notch1 siRNA. Overexpression of Prox1 siRNA upregulated Notch1 level and potentiated the morphine‐induced lineage changes.  Prox1  transcript level was regulated by direct interaction between miR‐181a and its 3′‐UTR sequence. In vitro and in vivo treatment with morphine resulted in an increase in miR‐181a level in hNPCs and mouse hippocampi, respectively. Overexpression of miR‐181a mimics reduced Prox1 levels, increased Notch1 levels, and enhanced hNPCs differentiation into astrocytes. Meanwhile, overexpression of the miR‐181a inhibitor raised Prox1 levels, decreased Notch1 levels, and subsequently blocked the morphine‐induced lineage changes. Thus, by modulating Prox1/Notch1 activities via miR‐181a, morphine influences the fate of differentiating hNPCs differentiation and therefore the ultimate quantities of mature neurons and astrocytes. S tem  C ells   2014;32:2961–2972

Morphine Modulates Mouse Hippocampal Progenitor Cell Lineages by Upregulating miR‐181a Level