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Morphine-Mediated Brain Region-Specific Astrocytosis Involves the ER Stress-Autophagy Axis

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Abstract

A recent study from our lab has revealed a link between morphine-mediated autophagy and synaptic impairment. The current study was aimed at investigating whether morphine-mediated activation of astrocytes involved the ER stress/autophagy axis. Our in vitro findings demonstrated upregulation of GFAP indicating astrocyte activation with a concomitant increase in the production of proinflammatory cytokines in morphine-exposed human astrocytes. Using both pharmacological and gene-silencing approaches, it was demonstrated that morphine-mediated defective autophagy involved upstream activation of ER stress with subsequent downstream astrocyte activation via the μ-opioid receptor (MOR). In vivo validation demonstrated preferential activation of ER stress/autophagy axis in the areas of the brain not associated with pain such as the basal ganglia, frontal cortex, occipital cortex, and the cerebellum of morphine-dependent rhesus macaques, and this correlated with increased astrocyte activation and neuroinflammation. Interventions aimed at blocking either the MOR or ER stress could thus likely be developed as promising therapeutic targets for abrogating morphine-mediated astrocytosis.

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References

  1. Stefano GB, Ptacek R, Kuzelova H, Kream RM (2012) Endogenous morphine: up-to-date review 2011. Folia Biol 58(2):49–56

    CAS  Google Scholar 

  2. Johnson F, Setnik B (2011) Morphine sulfate and naltrexone hydrochloride extended-release capsules: naltrexone release, pharmacodynamics, and tolerability. Pain Physician 14(4):391–406

    PubMed  Google Scholar 

  3. Ting S, Schug S (2016) The pharmacogenomics of pain management: prospects for personalized medicine. J Pain Res 9:49–56. https://doi.org/10.2147/JPR.S55595

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Morizio KM, Baum RA, Dugan A, Martin JE, Bailey AM (2017) Characterization and management of patients with heroin versus nonheroin opioid overdoses: experience at an Academic Medical Center. Pharmacotherapy 37(7):781–790. https://doi.org/10.1002/phar.1902

    Article  PubMed  CAS  Google Scholar 

  5. Friedman H, Eisenstein TK (2004) Neurological basis of drug dependence and its effects on the immune system. J Neuroimmunol 147(1–2):106–108. https://doi.org/10.1016/j.jneuroim.2003.10.022

    Article  PubMed  CAS  Google Scholar 

  6. Roy S, Wang J, Kelschenbach J, Koodie L, Martin J (2006) Modulation of immune function by morphine: implications for susceptibility to infection. J NeuroImmune Pharmacol 1(1):77–89. https://doi.org/10.1007/s11481-005-9009-8

    Article  PubMed  Google Scholar 

  7. Roy S, Barke RA, Loh HH (1998) MU-opioid receptor-knockout mice: role of mu-opioid receptor in morphine mediated immune functions. Brain Res Mol Brain Res 61(1–2):190–194. https://doi.org/10.1016/S0169-328X(98)00212-5

    Article  PubMed  CAS  Google Scholar 

  8. Roy S, Ninkovic J, Banerjee S, Charboneau RG, Das S, Dutta R, Kirchner VA, Koodie L et al (2011) Opioid drug abuse and modulation of immune function: consequences in the susceptibility to opportunistic infections. J NeuroImmune Pharmacol 6(4):442–465. https://doi.org/10.1007/s11481-011-9292-5

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chau DL, Walker V, Pai L, Cho LM (2008) Opiates and elderly: use and side effects. Clin Interv Aging 3(2):273–278. https://doi.org/10.2147/CIA.S1847

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Roy S, Chapin RB, Cain KJ, Charboneau RG, Ramakrishnan S, Barke RA (1997) Morphine inhibits transcriptional activation of IL-2 in mouse thymocytes. Cell Immunol 179(1):1–9. https://doi.org/10.1006/cimm.1997.1147

    Article  PubMed  CAS  Google Scholar 

  11. Roy S, Cain KJ, Charboneau RG, Barke RA (1998) Morphine accelerates the progression of sepsis in an experimental sepsis model. Adv Exp Med Biol 437:21–31. https://doi.org/10.1007/978-1-4615-5347-2_3

    Article  PubMed  CAS  Google Scholar 

  12. Dinda A, Gitman M, Singhal PC (2005) Immunomodulatory effect of morphine: therapeutic implications. Expert Opin Drug Saf 4(4):669–675. https://doi.org/10.1517/14740338.4.4.669

    Article  PubMed  CAS  Google Scholar 

  13. Liu HC, Anday JK, House SD, Chang SL (2004) Dual effects of morphine on permeability and apoptosis of vascular endothelial cells: morphine potentiates lipopolysaccharide-induced permeability and apoptosis of vascular endothelial cells. J Neuroimmunol 146(1–2):13–21. https://doi.org/10.1016/j.jneuroim.2003.09.016

    Article  PubMed  CAS  Google Scholar 

  14. Wen H, Lu Y, Yao H, Buch S (2011) Morphine induces expression of platelet-derived growth factor in human brain microvascular endothelial cells: implication for vascular permeability. PLoS One 6(6):e21707. https://doi.org/10.1371/journal.pone.0021707

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Hu S, Chao CC, Hegg CC, Thayer S, Peterson PK (2000) Morphine inhibits human microglial cell production of, and migration towards, RANTES. J Psychopharmacol 14(3):238–243. https://doi.org/10.1177/026988110001400307

    Article  PubMed  CAS  Google Scholar 

  16. Hu S, Sheng WS, Lokensgard JR, Peterson PK (2002) Morphine induces apoptosis of human microglia and neurons. Neuropharmacology 42(6):829–836. https://doi.org/10.1016/S0028-3908(02)00030-8

    Article  PubMed  CAS  Google Scholar 

  17. Horvath RJ, DeLeo JA (2009) Morphine enhances microglial migration through modulation of P2X4 receptor signaling. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 29(4):998–1005. https://doi.org/10.1523/JNEUROSCI.4595-08.2009

    Article  CAS  Google Scholar 

  18. Hauser KF, Stiene-Martin A, Mattson MP, Elde RP, Ryan SE, Godleske CC (1996) Mu-opioid receptor-induced Ca2+ mobilization and astroglial development: morphine inhibits DNA synthesis and stimulates cellular hypertrophy through a Ca(2+)-dependent mechanism. Brain Res 720(1–2):191–203. https://doi.org/10.1016/0006-8993(96)00103-5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Bruce-Keller AJ, Turchan-Cholewo J, Smart EJ, Geurin T, Chauhan A, Reid R, Xu R, Nath A et al (2008) Morphine causes rapid increases in glial activation and neuronal injury in the striatum of inducible HIV-1 Tat transgenic mice. Glia 56(13):1414–1427. https://doi.org/10.1002/glia.20708

    Article  PubMed  PubMed Central  Google Scholar 

  20. Tawfik VL, LaCroix-Fralish ML, Nutile-McMenemy N, DeLeo JA (2005) Transcriptional and translational regulation of glial activation by morphine in a rodent model of neuropathic pain. J Pharmacol Exp Ther 313(3):1239–1247. https://doi.org/10.1124/jpet.104.082420

    Article  PubMed  CAS  Google Scholar 

  21. Di Cesare Mannelli L, Corti F, Micheli L, Zanardelli M, Ghelardini C (2015) Delay of morphine tolerance by palmitoylethanolamide. Biomed Res Int 2015(894732):1–12. https://doi.org/10.1155/2015/894732

    Article  CAS  Google Scholar 

  22. Childers SR, Snyder SH (1978) Guanine nucleotides differentiate agonist and antagonist interactions with opiate receptors. Life Sci 23(7):759–761. https://doi.org/10.1016/0024-3205(78)90077-2

    Article  PubMed  CAS  Google Scholar 

  23. Childers SR, Creese I, Snowman AM, Synder SH (1979) Opiate receptor binding affected differentially by opiates and opioid peptides. Eur J Pharmacol 55(1):11–18. https://doi.org/10.1016/0014-2999(79)90142-0

    Article  PubMed  CAS  Google Scholar 

  24. Diaz A, Ruiz F, Florez J, Pazos A, Hurle MA (1995) Regulation of dihydropyridine-sensitive Ca++ channels during opioid tolerance and supersensitivity in rats. J Pharmacol Exp Ther 274(3):1538–1544

    PubMed  CAS  Google Scholar 

  25. Diaz A, Florez J, Pazos A, Hurle MA (2000) Opioid tolerance and supersensitivity induce regional changes in the autoradiographic density of dihydropyridine-sensitive calcium channels in the rat central nervous system. Pain 86(3):227–235. https://doi.org/10.1016/S0304-3959(00)00249-9

    Article  PubMed  CAS  Google Scholar 

  26. Nestler EJ (1996) Under siege: the brain on opiates. Neuron 16(5):897–900. https://doi.org/10.1016/S0896-6273(00)80110-5

    Article  PubMed  CAS  Google Scholar 

  27. Ippolito DL, Temkin PA, Rogalski SL, Chavkin C (2002) N-terminal tyrosine residues within the potassium channel Kir3 modulate GTPase activity of Galphai. J Biol Chem 277(36):32692–32696. https://doi.org/10.1074/jbc.M204407200

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Torrecilla M, Quillinan N, Williams JT, Wickman K (2008) Pre- and postsynaptic regulation of locus coeruleus neurons after chronic morphine treatment: a study of GIRK-knockout mice. Eur J Neurosci 28(3):618–624. https://doi.org/10.1111/j.1460-9568.2008.06348.x

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wickman K, Clapham DE (1995) Ion channel regulation by G proteins. Physiol Rev 75(4):865–885. https://doi.org/10.1152/physrev.1995.75.4.865

    Article  PubMed  CAS  Google Scholar 

  30. Torrecilla M, Marker CL, Cintora SC, Stoffel M, Williams JT, Wickman K (2002) G-protein-gated potassium channels containing Kir3.2 and Kir3.3 subunits mediate the acute inhibitory effects of opioids on locus ceruleus neurons. J Neurosci 22(11):4328–4334

  31. Volterra A, Meldolesi J (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6(8):626–640. https://doi.org/10.1038/nrn1722

    Article  PubMed  CAS  Google Scholar 

  32. Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7(1):41–53. https://doi.org/10.1038/nrn1824

  33. Hadera MG, Eloqayli H, Jaradat S, Nehlig A, Sonnewald U (2015) Astrocyte-neuronal interactions in epileptogenesis. J Neurosci Res 93(7):1157–1164. https://doi.org/10.1002/jnr.23584

    Article  PubMed  CAS  Google Scholar 

  34. Wang DD, Bordey A (2008) The astrocyte odyssey. Prog Neurobiol 86(4):342–367. https://doi.org/10.1016/j.pneurobio.2008.09.015

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Yan X, Shi ZF, LX X, Li JX, Wu M, Wang XX, Jia M, Dong LP et al (2017) Glutamate impairs mitochondria aerobic respiration capacity and enhances glycolysis in cultured rat astrocytes. Biomedical and environmental sciences : BES 30(1):44–51. https://doi.org/10.3967/bes2017.005

    Article  PubMed  Google Scholar 

  36. Hostenbach S, Cambron M, D'Haeseleer M, Kooijman R, De Keyser J (2014) Astrocyte loss and astrogliosis in neuroinflammatory disorders. Neurosci Lett 565:39–41. https://doi.org/10.1016/j.neulet.2013.10.012

    Article  PubMed  CAS  Google Scholar 

  37. Periyasamy P, Guo ML, Buch S (2016) Cocaine induces astrocytosis through ER stress-mediated activation of autophagy. Autophagy 12(8):1310–1329. https://doi.org/10.1080/15548627.2016.1183844

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Guilarte TR, Nihei MK, McGlothan JL, Howard AS (2003) Methamphetamine-induced deficits of brain monoaminergic neuronal markers: distal axotomy or neuronal plasticity. Neuroscience 122(2):499–513. https://doi.org/10.1016/S0306-4522(03)00476-7

    Article  PubMed  CAS  Google Scholar 

  39. Narita M, Suzuki M, Kuzumaki N, Miyatake M, Suzuki T (2008) Implication of activated astrocytes in the development of drug dependence: differences between methamphetamine and morphine. Ann N Y Acad Sci 1141(1):96–104. https://doi.org/10.1196/annals.1441.032

    Article  PubMed  CAS  Google Scholar 

  40. Slezak M, Korostynski M, Gieryk A, Golda S, Dzbek J, Piechota M, Wlazlo E, Bilecki W et al (2013) Astrocytes are a neural target of morphine action via glucocorticoid receptor-dependent signaling. Glia 61(4):623–635. https://doi.org/10.1002/glia.22460

    Article  PubMed  Google Scholar 

  41. Lazriev IL, Kiknadze GI, Kutateladze II, Nebieridze MI (2001) Effect of morphine on the number and branching of astrocytes in various regions of rat brain. Bull Exp Biol Med 131(3):248–250. https://doi.org/10.1023/A:1017699315355

    Article  PubMed  CAS  Google Scholar 

  42. Ikeda H, Miyatake M, Koshikawa N, Ochiai K, Yamada K, Kiss A, Donlin MJ, Panneton WM et al (2010) Morphine modulation of thrombospondin levels in astrocytes and its implications for neurite outgrowth and synapse formation. J Biol Chem 285(49):38415–38427. https://doi.org/10.1074/jbc.M110.109827

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Cai Y, Yang L, Hu G, Chen X, Niu F, Yuan L, Liu H, Xiong H et al (2016) Regulation of morphine-induced synaptic alterations: Role of oxidative stress, ER stress, and autophagy. J Cell Biol 215(2):245–258. https://doi.org/10.1083/jcb.201605065

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Kim KH, Lee MS (2014) Autophagy--a key player in cellular and body metabolism. Nat Rev Endocrinol 10(6):322–337. https://doi.org/10.1038/nrendo.2014.35

    Article  PubMed  CAS  Google Scholar 

  45. Ryter SW, Cloonan SM, Choi AM (2013) Autophagy: a critical regulator of cellular metabolism and homeostasis. Molecules and cells 36(1):7–16. https://doi.org/10.1007/s10059-013-0140-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Senft D, Ronai ZA (2015) UPR, autophagy, and mitochondria crosstalk underlies the ER stress response. Trends Biochem Sci 40(3):141–148. https://doi.org/10.1016/j.tibs.2015.01.002

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Lindholm D, Wootz H, Korhonen L (2006) ER stress and neurodegenerative diseases. Cell Death Differ 13(3):385–392. https://doi.org/10.1038/sj.cdd.4401778

    Article  PubMed  CAS  Google Scholar 

  48. Cai Y, Arikkath J, Yang L, Guo ML, Periyasamy P, Buch S (2016) Interplay of endoplasmic reticulum stress and autophagy in neurodegenerative disorders. Autophagy 12(2):225–244. https://doi.org/10.1080/15548627.2015.1121360

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M et al (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26(24):9220–9231. https://doi.org/10.1128/MCB.01453-06

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Guo ML, Liao K, Periyasamy P, Yang L, Cai Y, Callen SE, Buch S (2015) Cocaine-mediated microglial activation involves the ER stress-autophagy axis. Autophagy 11(7):995–1009. https://doi.org/10.1080/15548627.2015.1052205

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Roy S, Cain KJ, Chapin RB, Charboneau RG, Barke RA (1998) Morphine modulates NF kappa B activation in macrophages. Biochem Biophys Res Commun 245(2):392–396. https://doi.org/10.1006/bbrc.1998.8415

    Article  PubMed  CAS  Google Scholar 

  52. Zhao L, Zhu Y, Wang D, Chen M, Gao P, Xiao W, Rao G, Wang X et al (2010) Morphine induces Beclin 1- and ATG5-dependent autophagy in human neuroblastoma SH-SY5Y cells and in the rat hippocampus. Autophagy 6(3):386–394. https://doi.org/10.4161/auto.6.3.11289

    Article  PubMed  CAS  Google Scholar 

  53. El-Hage N, Rodriguez M, Dever SM, Masvekar RR, Gewirtz DA, Shacka JJ (2015) HIV-1 and morphine regulation of autophagy in microglia: limited interactions in the context of HIV-1 infection and opioid abuse. J Virol 89(2):1024–1035. https://doi.org/10.1128/JVI.02022-14

    Article  PubMed  CAS  Google Scholar 

  54. Kimura S, Noda T, Yoshimori T (2007) Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 3(5):452–460. https://doi.org/10.4161/auto.4451

    Article  PubMed  CAS  Google Scholar 

  55. Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9(7):671–675. https://doi.org/10.1038/nmeth.2089

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Pare EM, Monforte JR, Thibert RJ (1984) Morphine concentrations in brain tissue from heroin-associated deaths. J Anal Toxicol 8(5):213–216. https://doi.org/10.1093/jat/8.5.213

    Article  PubMed  CAS  Google Scholar 

  57. Yu B, Wenjun Z, Changsheng Y, Yuntao F, Jing M, Ben L, Hai Q, Guangwei X et al (2016) Preconditioning of endoplasmic reticulum stress protects against acrylonitrile-induced cytotoxicity in primary rat astrocytes: the role of autophagy. Neurotoxicology 55:112–121. https://doi.org/10.1016/j.neuro.2016.05.020

    Article  PubMed  CAS  Google Scholar 

  58. Cao L, Walker MP, Vaidya NK, Fu M, Kumar S, Kumar A (2016) Cocaine-mediated autophagy in astrocytes involves sigma 1 receptor, PI3K, mTOR, Atg5/7, Beclin-1 and induces type II programed cell death. Mol Neurobiol 53(7):4417–4430. https://doi.org/10.1007/s12035-015-9377-x

    Article  PubMed  CAS  Google Scholar 

  59. Kubota K, Niinuma Y, Kaneko M, Okuma Y, Sugai M, Omura T, Uesugi M, Uehara T et al (2006) Suppressive effects of 4-phenylbutyrate on the aggregation of Pael receptors and endoplasmic reticulum stress. J Neurochem 97(5):1259–1268. https://doi.org/10.1111/j.1471-4159.2006.03782.x

    Article  PubMed  CAS  Google Scholar 

  60. Rozpedek W, Pytel D, Mucha B, Leszczynska H, Diehl JA, Majsterek I (2016) The role of the PERK/eIF2alpha/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Curr Mol Med 16(6):533–544. https://doi.org/10.2174/1566524016666160523143937

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Fukagawa H, Koyama T, Kakuyama M, Fukuda K (2013) Microglial activation involved in morphine tolerance is not mediated by toll-like receptor 4. J Anesth 27(1):93–97. https://doi.org/10.1007/s00540-012-1469-4

    Article  PubMed  Google Scholar 

  62. Tauber SC, Staszewski O, Prinz M, Weis J, Nolte K, Bunkowski S, Bruck W, Nau R (2016) HIV encephalopathy: glial activation and hippocampal neuronal apoptosis, but limited neural repair. HIV Med 17(2):143–151. https://doi.org/10.1111/hiv.12288

    Article  PubMed  CAS  Google Scholar 

  63. Wang X, Loram LC, Ramos K, de Jesus AJ, Thomas J, Cheng K, Reddy A, Somogyi AA et al (2012) Morphine activates neuroinflammation in a manner parallel to endotoxin. Proc Natl Acad Sci U S A 109(16):6325–6330. https://doi.org/10.1073/pnas.1200130109

    Article  PubMed  PubMed Central  Google Scholar 

  64. Wan J, Ma J, Anand V, Ramakrishnan S, Roy S (2015) Morphine potentiates LPS-induced autophagy initiation but inhibits autophagosomal maturation through distinct TLR4-dependent and independent pathways. Acta Physiol 214(2):189–199. https://doi.org/10.1111/apha.12506

    Article  CAS  Google Scholar 

  65. Pan Y, Sun X, Jiang L, Hu L, Kong H, Han Y, Qian C, Song C et al (2016) Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation. J Neuroinflammation 13(1):294. https://doi.org/10.1186/s12974-016-0754-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Dalvi P, Sharma H, Chinnappan M, Sanderson M, Allen J, Zeng R, Choi A, O’Brien-Ladner A et al (2016) Enhanced autophagy in pulmonary endothelial cells on exposure to HIV-Tat and morphine: role in HIV-related pulmonary arterial hypertension. Autophagy 12(12):2420–2438. https://doi.org/10.1080/15548627.2016.1238551

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Dever SM, Rodriguez M, Lapierre J, Costin BN, El-Hage N (2015) Differing roles of autophagy in HIV-associated neurocognitive impairment and encephalitis with implications for morphine co-exposure. Front Microbiol 6:653. https://doi.org/10.3389/fmicb.2015.00653

    Article  PubMed  PubMed Central  Google Scholar 

  68. Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, Omori H, Noda T et al (2008) Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456(7219):264–268. https://doi.org/10.1038/nature07383

    Article  PubMed  CAS  Google Scholar 

  69. Paul S, Kashyap AK, Jia W, He YW, Schaefer BC (2012) Selective autophagy of the adaptor protein Bcl10 modulates T cell receptor activation of NF-kappaB. Immunity 36(6):947–958. https://doi.org/10.1016/j.immuni.2012.04.008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Henckaerts L, Cleynen I, Brinar M, John JM, Van Steen K, Rutgeerts P, Vermeire S (2011) Genetic variation in the autophagy gene ULK1 and risk of Crohn’s disease. Inflamm Bowel Dis 17(6):1392–1397. https://doi.org/10.1002/ibd.21486

    Article  PubMed  Google Scholar 

  71. Nakamura S, Yoshimori T (2017) New insights into autophagosome-lysosome fusion. J Cell Sci 130(7):1209–1216. https://doi.org/10.1242/jcs.196352

    Article  PubMed  CAS  Google Scholar 

  72. Button RW, Roberts SL, Willis TL, Hanemann CO, Luo S (2017) Accumulation of autophagosomes confers cytotoxicity. J Biol Chem 292(33):13599–13614. https://doi.org/10.1074/jbc.M117.782276

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Hori I, Otomo T, Nakashima M, Miya F, Negishi Y, Shiraishi H, Nonoda Y, Magara S et al (2017) Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement. Sci Rep 7(1):3552. https://doi.org/10.1038/s41598-017-02840-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Schroder M (2008) Endoplasmic reticulum stress responses. Cell Mol Life Sci 65(6):862–894. https://doi.org/10.1007/s00018-007-7383-5

    Article  PubMed  CAS  Google Scholar 

  75. Kroemer G, Marino G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40(2):280–293. https://doi.org/10.1016/j.molcel.2010.09.023

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. B'Chir W, Maurin AC, Carraro V, Averous J, Jousse C, Muranishi Y, Parry L, Stepien G et al (2013) The eIF2alpha/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res 41(16):7683–7699. https://doi.org/10.1093/nar/gkt563

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Kouroku Y, Fujita E, Tanida I, Ueno T, Isoai A, Kumagai H, Ogawa S, Kaufman RJ et al (2007) ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ 14(2):230–239. https://doi.org/10.1038/sj.cdd.4401984

    Article  PubMed  CAS  Google Scholar 

  78. Hoyer-Hansen M, Bastholm L, Szyniarowski P, Campanella M, Szabadkai G, Farkas T, Bianchi K, Fehrenbacher N et al (2007) Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol Cell 25(2):193–205. https://doi.org/10.1016/j.molcel.2006.12.009

    Article  PubMed  CAS  Google Scholar 

  79. Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L, Brunner T, Simon HU (2006) Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 8(10):1124–1132. https://doi.org/10.1038/ncb1482

    Article  PubMed  CAS  Google Scholar 

  80. Liu S, Sarkar C, Dinizo M, Faden AI, Koh EY, Lipinski MM, Wu J (2015) Disrupted autophagy after spinal cord injury is associated with ER stress and neuronal cell death. Cell Death Dis 6(1):e1582. https://doi.org/10.1038/cddis.2014.527

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Ye J, Jiang Z, Chen X, Liu M, Li J, Liu N (2017) The role of autophagy in pro-inflammatory responses of microglia activation via mitochondrial reactive oxygen species in vitro. J Neurochem 142(2):215–230. https://doi.org/10.1111/jnc.14042

    Article  PubMed  CAS  Google Scholar 

  82. Aoe T (2013) Endoplasmic reticulum stress and opioid tolerance withdrawal. Masui the Japanese Journal of Anesthesiology 62(3):283–289

    PubMed  Google Scholar 

  83. Dobashi T, Tanabe S, Jin H, Nishino T, Aoe T (2010) Valproate attenuates the development of morphine antinociceptive tolerance. Neurosci Lett 485(2):125–128. https://doi.org/10.1016/j.neulet.2010.08.084

    Article  PubMed  CAS  Google Scholar 

  84. Ghavimi H, Hassanzadeh K, Maleki-Dizaji N, Azarfardian A, Ghasami S, Zolali E, Charkhpour M (2014) Pioglitazone prevents morphine antinociception tolerance and withdrawal symptoms in rats. Naunyn Schmiedeberg's Arch Pharmacol 387(9):811–821. https://doi.org/10.1007/s00210-014-0996-y

    Article  CAS  Google Scholar 

  85. Campbell LA, Avdoshina V, Rozzi S, Mocchetti I (2013) CCL5 and cytokine expression in the rat brain: differential modulation by chronic morphine and morphine withdrawal. Brain Behav Immun 34:130–140. https://doi.org/10.1016/j.bbi.2013.08.006

    Article  PubMed  CAS  Google Scholar 

  86. Amaral GF, Dossa PD, Viebig LB, Konno FTC, Consoli A, Martins MFM, Viani FC, Bondan EF (2016) Astrocytic expression of GFAP and serum levels of IL-12 and TNF-± in rats treated with different pain relievers. Brazilian Journal of Pharmaceutical Sciences 52(4):623–633. https://doi.org/10.1590/s1984-82502016000400006

    Article  Google Scholar 

  87. Beitner-Johnson D, Guitart X, Nestler EJ (1993) Glial fibrillary acidic protein and the mesolimbic dopamine system: regulation by chronic morphine and Lewis-Fischer strain differences in the rat ventral tegmental area. J Neurochem 61(5):1766–1773. https://doi.org/10.1111/j.1471-4159.1993.tb09814.x

    Article  PubMed  CAS  Google Scholar 

  88. Patel NA, Romero AA, Zadina JE, Chang SL (1996) Chronic exposure to morphine attenuates expression of interleukin-1 beta in the rat hippocampus. Brain Res 712(2):340–344. https://doi.org/10.1016/0006-8993(95)01575-2

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We are grateful to Drs. Guoku Hu, Ernest Chivero, Annadurai Thangaraj, and Mr. Ke Liao for their useful discussions and to Ms. Fang Niu and Ms. Yeon Hee Kook for their technical assistance.

Funding

This work was supported by grants DA033614, DA035203, and DA041751 (SB) from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA

    Susmita Sil, Palsamy Periyasamy, Ming-Lei Guo, Shannon Callen & Shilpa Buch

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  1. Susmita Sil
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  2. Palsamy Periyasamy
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  3. Ming-Lei Guo
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Correspondence to Shilpa Buch.

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Sil, S., Periyasamy, P., Guo, ML. et al. Morphine-Mediated Brain Region-Specific Astrocytosis Involves the ER Stress-Autophagy Axis. Mol Neurobiol 55, 6713–6733 (2018). https://doi.org/10.1007/s12035-018-0878-2

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