Opioids intrinsically inhibit the genesis of mouse cerebellar granule neuron precursors in vitro: differential impact of mu and delta receptor activation on proliferation and neurite elongation

Although opioids are known to affect neurogenesis in vivo, it is uncertain the extent to which opioids directly or indirectly affect the proliferation , differentiation or death of neuronal precursors. To address these questio ns, the intrinsic role of the opioid system in neurogenesis was systematica lly explored in cerebellar external granular layer (EGL) neuronal precursor s isolated from postnatal mice and maintained in vitro. Isolated neuronal p recursors expressed proenkephalin-derived peptides, as well as specific mu and delta, but negligible kappa, opioid receptors. The developmental effect s of opioids were highly selective. Morphine-induced mu receptor activation inhibited DNA synthesis, while a preferential delta(2)-receptor agonist ([ D-Ala(2)]-deltorphin II) or Met-enkephalin, but not the delta(1) agonist [D -Pen(2), D-Pen(5)]-enkephalin, inhibited differentiation within the same ne uronal population. If similar patterns occur in the developing cerebellum, spatiotemporal differences in endogenous mu and delta opioid ligand-recepto r interactions may coordinate distinct aspects of granule neuron maturation . The data additionally suggest that perinatal exposure to opiate drugs of abuse directly interfere with cerebellar maturation by disrupting normal op ioid signalling and inhibiting the proliferation of granule neuron precurso rs.