μ-Opioid receptor attenuates Aβ oligomers-induced neurotoxicity through mTOR signaling. 2015

Yan Wang, and Yan-Xia Wang, and Ting Liu, and Ping-Yee Law, and Horace H Loh, and Yu Qiu, and Hong-Zhuan Chen
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.

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.

UI MeSH Term Description Entries
D009020 Morphine The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. Morphine Sulfate,Duramorph,MS Contin,Morphia,Morphine Chloride,Morphine Sulfate (2:1), Anhydrous,Morphine Sulfate (2:1), Pentahydrate,Oramorph SR,SDZ 202-250,SDZ202-250,Chloride, Morphine,Contin, MS,SDZ 202 250,SDZ 202250,SDZ202 250,SDZ202250,Sulfate, Morphine
D009294 Narcotics Agents that induce NARCOSIS. Narcotics include agents that cause somnolence or induced sleep (STUPOR); natural or synthetic derivatives of OPIUM or MORPHINE or any substance that has such effects. They are potent inducers of ANALGESIA and OPIOID-RELATED DISORDERS. Analgesics, Narcotic,Narcotic Analgesics,Narcotic,Narcotic Effect,Narcotic Effects,Effect, Narcotic,Effects, Narcotic
D009474 Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM. Nerve Cells,Cell, Nerve,Cells, Nerve,Nerve Cell,Neuron
D010446 Peptide Fragments Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques. Peptide Fragment,Fragment, Peptide,Fragments, Peptide
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D002540 Cerebral Cortex The thin layer of GRAY MATTER on the surface of the CEREBRAL HEMISPHERES that develops from the TELENCEPHALON and folds into gyri and sulci. It reaches its highest development in humans and is responsible for intellectual faculties and higher mental functions. Allocortex,Archipallium,Cortex Cerebri,Cortical Plate,Paleocortex,Periallocortex,Allocortices,Archipalliums,Cerebral Cortices,Cortex Cerebrus,Cortex, Cerebral,Cortical Plates,Paleocortices,Periallocortices,Plate, Cortical
D004745 Enkephalins One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. Enkephalin
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015153 Blotting, Western Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes. Immunoblotting, Western,Western Blotting,Western Immunoblotting,Blot, Western,Immunoblot, Western,Western Blot,Western Immunoblot,Blots, Western,Blottings, Western,Immunoblots, Western,Immunoblottings, Western,Western Blots,Western Blottings,Western Immunoblots,Western Immunoblottings

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