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

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Abstract
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 questions, the intrinsic role of the opioid system in neurogenesis was systematically explored in cerebellar external granular layer (EGL) neuronal precursors isolated from postnatal mice and maintained in vitro. Isolated neuronal precursors expressed proenkephalin‐derived peptides, as well as specific μ and δ, but negligible κ, opioid receptors. The developmental effects of opioids were highly selective. Morphine‐induced μ receptor activation inhibited DNA synthesis, while a preferential δ2‐receptor agonist ([d‐Ala2]‐deltorphin II) or Met‐enkephalin, but not the δ1 agonist [d‐Pen2, d‐Pen5]‐enkephalin, inhibited differentiation within the same neuronal population. If similar patterns occur in the developing cerebellum, spatiotemporal differences in endogenous μ and δ opioid ligand–receptor 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 opioid signalling and inhibiting the proliferation of granule neuron precursors.