Fig. 3 |. Neurogenesis and biased MOP agonism in NSPC proliferation and differentiation.

a | The subgranuίar zone (SGZ) of the dentate gyrus (DG) provides a unique microenvironment where adult neural stem and progenitor cells (NSPCs) undergo several consecutive developmental stages characterized by different cell types¹⁷. NSPCs are derived from embryonic stem cells that survived in the adult SGZ. NSPCs self-renew and include type 1 radiaί-gίia-ίike (RGL) stem cells, which give rise to intermediate progenitor cells type 2a and 2b. These type 2 cells can generate type 3 progenitors (neuroblasts), which are capable of differentiating into immature neurons. During maturation, immature neurons become granule neurons and are functionally integrated into the DG pre-existing circuit. Type 2b and type 3 cells, immature and mature neurons, express the transcription factors NeuroD1 and Prox1, which are specific to granule cell development³². Notch 1 promotes astroglial but not neuronal differentiation¹⁷. b | μ-Opioid peptide receptor (MOP) agonists (such as morphine) inhibit NSPC proliferation mainly by slowing the cell cycle G2/M phase transition (prolonged S phase) in mouse embryonic NSPCs²⁸, though details regarding the mechanism remain elusive. Other pathways leading to stagnating proliferation (indicated by the dashed arrow and question mark) might exist. Morphine induces extraceίίuίar-signaί-reguίated kinase (ERK) phosphorylation in a PKCε-dependent manner, and the activated ERK in turn phosphorylates TRBP, which is a stabilizer of Dicer, the essential enzyme for microRNA maturation⁴³. The mature miR-181a-5p then inhibits the transcription factor Prox1, an inhibitor of another transcription factor, Notch1. Thus, increased Notch1 expression mediates the inhibition of neuronal differentiation¹⁵. The inhibition of neurogenic differentiation 1 (NeuroD1) phosphorylation is another pathway by which morphine affects the transition of NSPCs into immature neurons in adult mice¹⁶. It is inferred that although both morphine and fentanyl affect NeuroD1 phosphorylation by inhibiting CaMKIIα, a crucial enzyme that catalyses NeuroD1 phosphorylation, fentanyl was able to activate NeuroD1 via the β-arrestin-ERK-miR-190 pathway, thus reflecting the biased antagonism of MOP agonists⁴⁴. Involvement of this pathway has been demonstrated only in cultured primary neurons⁷⁴.