title: μ-Opioid receptor attenuates Aβ oligomers-induced neurotoxicity through mTOR signaling.
abstract: OBJECTIVE
  μ-opioid receptor (OPRM1) exerts many functions such as antinociception, neuroprotection, and hippocampal plasticity. A body of evidence has shown that OPRM1 activation could stimulate downstream effectors of mechanistic/mammalian target of rapamycin (mTOR). However, it is not clear whether OPRM1 protects neurons against β-amyloid peptide (Aβ) neurotoxicity through mTOR signaling.
  
  
  METHODS
  The effects of OPRM1 activation on Aβ 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 OPRM1 activation by morphine were measured by immunoblotting their phosphorylation status.
  
  
  RESULTS
  Morphine dose-dependently attenuated Aβ oligomers-induced neurotoxicity. Aβ oligomers downregulated mTOR signaling. Morphine significantly rescued mTOR signaling by reversal of Aβ 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 OPRM1 selective antagonist and phosphatidylinositol 3-kinases (PI3K), Akt and mTOR inhibitors. Furthermore, endogenous opioids-enkaphalins also attenuated Aβ oligomers-induced neurotoxicity.
  
  
  CONCLUSIONS
  Our findings demonstrated OPRM1 activation attenuated Aβ oligomers-induced neurotoxicity through mTOR signaling. It may provide new insight into the pathological process and useful strategy for therapeutic interventions against Aβ neurotoxicity.
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Yan-Xia
authors.initials: YX
authors.lastname: Wang
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.forename: Ping-Yee
authors.initials: PY
authors.lastname: Law
authors.forename: Horace H
authors.initials: HH
authors.lastname: Loh
authors.forename: Yu
authors.initials: Y
authors.lastname: Qiu
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D049108:Cell Enlargement; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology*; D004745:Enkephalins / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D004745:Enkephalins; D009020:Morphine; D009294:Narcotics; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017450:Receptors, Opioid, mu; D058570:TOR Serine-Threonine Kinases; C485765:Oprm1 protein, rat; C078592:amyloid beta-protein (1-40); C546845:mTOR protein, rat
keywords: Alzheimer's disease; Mechanistic/mammalian target of rapamycin; β-Amyloid peptide; μ-Opioid receptor