μ ‐Opioid Receptor Attenuates A β Oligomers‐Induced Neurotoxicity Through mTOR Signaling

Summary Aims μ ‐opioid receptor ( OPRM 1) exerts many functions such as antinociception, neuroprotection, and hippocampal plasticity. A body of evidence has shown that OPRM 1 activation could stimulate downstream effectors of mechanistic/mammalian target of rapamycin ( mTOR ). However, it is not clear whether OPRM 1 protects neurons against β ‐amyloid peptide (A β ) neurotoxicity through mTOR signaling. Methods The effects of OPRM 1 activation on A β oligomers‐induced neurotoxicity were assessed by cell viability and neurite outgrowth assay in primary cultured cortical neurons. The activities of mTOR , protein kinase B (Akt) and p70 ribosomal S6 kinase (p70 S6k) upon OPRM 1 activation by morphine were measured by immunoblotting their phosphorylation status. Results Morphine dose‐dependently attenuated A β oligomers‐induced neurotoxicity. A β oligomers downregulated mTOR signaling. Morphine significantly rescued mTOR signaling by reversal of A β oligomers’ effect on mTOR and its upstream signaling molecule Akt, as well as its downstream molecule p70 S6k. Moreover, the neuroprotective effect of morphine could be reversed by OPRM 1 selective antagonist and phosphatidylinositol 3‐kinases (PI3K), Akt and mTOR inhibitors. Furthermore, endogenous opioids–enkaphalins also attenuated A β oligomers‐induced neurotoxicity. Conclusions Our findings demonstrated OPRM 1 activation attenuated A β oligomers‐induced neurotoxicity through mTOR signaling. It may provide new insight into the pathological process and useful strategy for therapeutic interventions against A β neurotoxicity.