Morphine coordinates SST and PV interneurons in the prelimbic cortex to synergistically disinhibit pyramidal neurons and enhance reward

Opioids such as morphine are clinic analgesics while are addictive. Morphine exposure modifies functional interactions between neurons, while the cellular and molecular basis of morphine in assembling heterogeneous interneurons (INs) for disinhibition and reward, is unclear. Using an approach combining optogenetics, electrophysiology, and cell type-specific RNA-seq etc, we found that, morphine decreases the inhibitory synaptic transmission from parvalbumin+ (PV)-INs, but not from somatostatin+ (SST)-INs onto pyramidal neurons in mouse prelimbic cortex (PrL) via -opioid receptor (MOR). Meanwhile, morphine increases the neurite complexity of SST-INs, enhances their inhibitory inputs onto PV-INs and thus disinhibits pyramidal neurons via Rac1 pathway. Rac1 activity in SST-INs is required for both morphine-induced conditioned place preference (CPP) and locomotor activity, while MOR in PV-INs is required for morphine-induced locomotor activity. Our results reveal a disinhibitory architecture including SST-INs and PV-INs, which is specifically coordinated by morphine to synergistically disinhibit pyramidal neurons of PrL and enhance reward.