Morphine and DAMGO produce an opposite effect on presynaptic glutamate release via different downstream pathways of mu opioid receptors in the basolateral amygdala

摘要

Increasing evidence demonstrates that different opioids, while acting mu opioid receptors, can activate distinct downstream responses, a phenomenon termed functional selectivity or biased agonism. The present study designed experiments to test whether the mu receptor agonist morphine and D-Ala~2, N-Me-Phe~4, Gly~5-ol-enkephalin (DAMGO) had a different effect on presynaptic glutamate release in the basolateral amygdala (BLA) and whether this difference was due to their biased agonism at mu receptors. The results showed that DAMGO markedly decreased the frequency of sEPSCs in pyramidal cells of BLA. The concentration-dependence experiment showed that DAMGO dose-dependently decreased the frequency of sEPSCs. Morphine markedly increased the frequency of sEPSCs in pyramidal cells of BLA. The concentration-dependence experiment showed that morphine dose-dependently increased the frequency of sEPSCs. We also used PPF of EPSC as another indicator of presynaptic glutamate release to confirm the opposite effect of morphine and DAMGO on the glutamate release. Further mechanism studies showed that the opposite effect of morphine and DAMGO on the glutamate release was via the activation of mu receptors, but the downstream signaling pathways of mu receptors were different: DAMGO inhibited the glutamate release via mu receptor-Gi protein- PLA_2-AA signaling pathway, whereas morphine promoted the glutamate release via mu receptor-Gi protein-PKC-ERK1/2-synapsin I signaling pathway.