Abstract
Certain experimental models support morphine can play a beneficial role against damage in the neuronal system. In this study, we find morphine as well as endomorphin-1 and endomorphin-2 can protect against intracellular amyloid β (iAβ) toxicity in human and rat primary neuronal cultures and in rat brains in vivo. Morphine reverses the electrophysiological changes induced by iAβ, including current density, resting membrane potential and capacitance. Also morphine improves the spatial memory performance in rats infected by iAβ packaged virus and in APP/PS1 mice in Morris water maze tests. Morphine protection is mediated through inducing estradiol release in hippocampal neurons measured by ELISA and liquid chromatography-mass spectrometry, possibly by increasing P450 cytochrome aromatase activity. Released estradiol induces upregulation of heat shock protein 70 (Hsp70). Hsp70 protects against intracellular amyloid toxicity by rescuing proteasomal activity which is impaired by iAβ. This is the first time, to our knowledge, that induction of estradiol release in hippocampal neurons by morphine is reported. Our data may contribute to both Alzheimer's disease therapy and pain clinics where morphine is widely used.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / pathology
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Alzheimer Disease / prevention & control
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Amyloid beta-Peptides / toxicity
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Amyloid beta-Protein Precursor / genetics
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Analysis of Variance
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Animals
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Animals, Newborn
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Brain / cytology
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Chromatography, Liquid
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Disease Models, Animal
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Enzyme-Linked Immunosorbent Assay
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Estradiol / metabolism*
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Fetus
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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HSP70 Heat-Shock Proteins / metabolism*
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Humans
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In Situ Nick-End Labeling
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Male
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Maze Learning / drug effects
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Membrane Potentials / drug effects
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Membrane Potentials / genetics
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Mice
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Mice, Transgenic
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Microinjections / methods
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Morphine / pharmacology*
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Narcotics / pharmacology*
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Neurons / drug effects*
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Oligopeptides / therapeutic use
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Patch-Clamp Techniques
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Peptide Fragments / toxicity
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Presenilin-1 / genetics
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Rats
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Rats, Sprague-Dawley
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Spectrometry, Mass, Electrospray Ionization
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Transfection
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Up-Regulation / drug effects*
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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HSP70 Heat-Shock Proteins
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Narcotics
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Oligopeptides
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PSEN1 protein, human
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Peptide Fragments
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Presenilin-1
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amyloid beta-protein (1-42)
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endomorphin 1
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enhanced green fluorescent protein
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Green Fluorescent Proteins
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endomorphin 2
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Estradiol
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Morphine