title: Morphine protects against intracellular amyloid toxicity by inducing estradiol release and upregulation of Hsp70.
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.
authors.affiliation: Laboratory of Neurobiology and State Key Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences and College of Urban and Environmental Sciences, Peking University, Beijing 100871, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Cui
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Qiping
authors.initials: Q
authors.lastname: Dong
authors.forename: Shimin
authors.initials: S
authors.lastname: Wu
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Xiao
authors.forename: Jianying
authors.initials: J
authors.lastname: Hu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chai
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000378:metabolism*; D005333:Fetus; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008845:Microinjections / Q000379:methods; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D009842:Oligopeptides / Q000627:therapeutic use; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000633:toxicity; D053764:Presenilin-1 / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018840:HSP70 Heat-Shock Proteins; D009294:Narcotics; D009842:Oligopeptides; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); C105293:endomorphin 1; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C105294:endomorphin 2; D004958:Estradiol; D009020:Morphine
references.citation: Brain Res Brain Res Rev. 1996 Jun;22(1):1-26
references.pmid: 8871783
references.citation: Proc Natl Acad Sci U S A. 1986 Apr;83(8):2496-500
references.pmid: 3458212
references.citation: Biochemistry. 1998 Jul 28;37(30):10757-65
references.pmid: 9692966
references.citation: Methods Find Exp Clin Pharmacol. 2000 Dec;22(10):753-5
references.pmid: 11346897
references.citation: Drugs Aging. 1997 Aug;11(2):87-95
references.pmid: 9259172
references.citation: J Cell Biol. 2002 Feb 4;156(3):519-29
references.pmid: 11815632
references.citation: Zhong Yao Cai. 2008 Nov;31(11):1675-8
references.pmid: 19260278
references.citation: J Am Geriatr Soc. 1996 Jul;44(7):865-70
references.pmid: 8675940
references.citation: Neuropharmacology. 2005 Dec;49(8):1160-9
references.pmid: 16098996
references.citation: Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15130-5
references.pmid: 8986775
references.citation: J Biol Chem. 1998 Mar 27;273(13):7523-8
references.pmid: 9516453
references.citation: J Neurosci. 2004 Jun 30;24(26):5913-21
references.pmid: 15229239
references.citation: Exp Neurol. 2003 Nov;184(1):247-63
references.pmid: 14637096
references.citation: Prog Neurobiol. 2007 Oct;83(3):131-9
references.pmid: 17889422
references.citation: J Neurosci. 2004 Jun 9;24(23):5315-21
references.pmid: 15190103
references.citation: Med Sci Monit. 2005 Oct;11(10):BR357-66
references.pmid: 16192893
references.citation: Neuroscientist. 2008 Dec;14(6):561-70
references.pmid: 18349442
references.citation: J Neurosurg Anesthesiol. 2006 Apr;18(2):119-24
references.pmid: 16628065
references.citation: Mol Cancer Ther. 2006 Mar;5(3):611-20
references.pmid: 16546975
references.citation: Endocrinology. 1999 Aug;140(8):3843-52
references.pmid: 10433246
references.citation: Neurology. 1998 Apr;50(4):996-1002
references.pmid: 9566385
references.citation: Am J Physiol Heart Circ Physiol. 2001 Jul;281(1):H404-10
references.pmid: 11406509
references.citation: J Pharmacol Exp Ther. 1998 Jun;285(3):1266-73
references.pmid: 9618432
references.citation: Physiol Behav. 2008 Feb 27;93(3):502-11
references.pmid: 18031772
references.citation: J Pharmacol Exp Ther. 1988 Sep;246(3):1033-9
references.pmid: 2843624
references.citation: Annu Rev Neurosci. 1998;21:479-505
references.pmid: 9530504
references.citation: J Neurosci. 1995 Dec;15(12):7837-46
references.pmid: 8613723
references.citation: Neurology. 1997 Jun;48(6):1517-21
references.pmid: 9191758
references.citation: J Neuropathol Exp Neurol. 2006 Oct;65(10):945-52
references.pmid: 17021399
references.citation: Am J Pathol. 2004 Feb;164(2):679-88
references.pmid: 14742271
references.citation: JAMA. 2003 May 28;289(20):2651-62
references.pmid: 12771112
references.citation: J Am Geriatr Soc. 2004 Feb;52(2):182-6
references.pmid: 14728625
references.citation: FASEB J. 2000 Aug;14(11):1508-17
references.pmid: 10928985
references.citation: JAMA. 2000 Jul 19;284(3):307-8
references.pmid: 10891958
references.citation: Curr Opin Investig Drugs. 2002 May;3(5):768-73
references.pmid: 12090551
references.citation: Eur J Neurosci. 2010 Aug;32(4):550-9
references.pmid: 20646065
references.citation: J Immunol. 2007 Jul 15;179(2):1198-209
references.pmid: 17617613
references.citation: Curr Alzheimer Res. 2008 Dec;5(6):555-61
references.pmid: 19075582
references.citation: Biochem Pharmacol. 2001 Apr 1;61(7):779-86
references.pmid: 11274962
references.citation: JAMA. 1998 Mar 4;279(9):688-95
references.pmid: 9496988
references.citation: Ann Neurol. 2004 Jun;55(6):801-14
references.pmid: 15174014
references.citation: Semin Reprod Med. 2005 May;23(2):172-9
references.pmid: 15852203
references.citation: Neurosci Lett. 2009 Oct 25;462(3):294-9
references.pmid: 19616060
references.citation: Neuroimage. 2001 Oct;14(4):789-801
references.pmid: 11554798
references.citation: Neuroreport. 2008 Dec 3;19(18):1745-9
references.pmid: 18849879
references.citation: Glia. 2010 Oct;58(13):1630-9
references.pmid: 20578038
references.citation: J Cell Biol. 2008 Jan 28;180(2):417-26
references.pmid: 18227283
references.citation: J Biol Chem. 1989 Jan 5;264(1):431-6
references.pmid: 2535842
references.citation: Med Sci Monit. 2005 Nov;11(11):BR386-96
references.pmid: 16258387
references.citation: Hippocampus. 2006;16(5):464-71
references.pmid: 16502389
references.citation: JAMA. 2003 May 28;289(20):2663-72
references.pmid: 12771113
references.citation: Cell Stress Chaperones. 2004 Summer;9(2):182-97
references.pmid: 15497504