Skip to main content

Advertisement

SpringerLink
Log in

Morphine Inhibited the Rat Neural Stem Cell Proliferation Rate by Increasing Neuro Steroid Genesis

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Up to present, a large number of reports unveiled exacerbating effects of both long- and short-term administration of morphine, as a potent analgesic agent, on opium-addicted individuals and a plethora of cell kinetics, although contradictory effect of morphine on different cells have been introduced until yet. To address the potent modulatory effect of morphine on neural multipotent precursors with emphasis on endogenous sex-related neurosteroids biosynthesis, we primed the rat neural stem cells isolated from embryonic rat telencephalon to various concentrations of morphine including 10, 20, 50 and 100 µM alone or in combination with naloxone (100 µM) over period of 72 h. Flow cytometric Ki-67 expression and Annexin-V/PI based necrosis and apoptosis of exposed cells were evaluated. The total content of dihydrotestosterone and estradiol in cell supernatant was measured by ELISA. According on obtained data, both concentration- and time-dependent decrement of cell viability were orchestrated thorough down-regulation of ki-67 and simultaneous up-regulation of Annexin-V. On the other hand, the addition of naloxone (100 µM), as Mu opiate receptor antagonist, could blunt the morphine-induced adverse effects. It also well established that time-course exposure of rat neural stem cells with morphine potently could accelerate the endogenous dihydrotestosterone and estradiol biosynthesis. Interestingly, naloxone could consequently attenuate the enhanced neurosteroidogenesis time-dependently. It seems that our results discover a biochemical linkage between an accelerated synthesis of sex-related steroids and rat neural stem cells viability.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Zhuo M, Wu G, Wu L-J (2011) Neuronal and microglial mechanisms of neuropathic pain. Mol Brain 4:31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Abs R, Verhelst J, Maeyaert J, Van Buyten J-P, Opsomer F, Adriaensen H, Verlooy J, Van Havenbergh T, Smet M, Van Acker K (2000) Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab 85:2215–2222

    Article  CAS  PubMed  Google Scholar 

  3. Hutchinson MR, Bland ST, Johnson KW, Rice KC, Maier SF, Watkins LR (2007) Opioid-induced glial activation: mechanisms of activation and implications for opioid analgesia, dependence, and reward. Sci World J 7:98–111

    Article  Google Scholar 

  4. Mao J, Sung B, Ji R-R, Lim G (2002) Neuronal apoptosis associated with morphine tolerance: evidence for an opioid-induced neurotoxic mechanism. J Neurosci 22:7650–7661

    CAS  PubMed  Google Scholar 

  5. Chau DL, Walker V, Pai L, Cho LM (2008) Opiates and elderly: use and side effects. Clin Interv Aging 3(2):273–278

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Gil M, Sala M, Anguera I, Chapinal O, Cervantes M, Guma JR, Segura F (2003) QT prolongation and torsades de pointes in patients infected with human immunodeficiency virus and treated with methadone. Am J Cardiol 92(8):995–997

    Article  CAS  PubMed  Google Scholar 

  7. Cherny N, Ripamonti C, Pereira J, Davis C, Fallon M, McQuay H, Mercadante S, Pasternak G, Ventafridda V (2001) Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol 19:2542–2554

    CAS  PubMed  Google Scholar 

  8. Bueno L, Fioramonti J (1988) 7 Action of opiates on gastrointestinal function. Baillieres Clin Gastroenterol 2(1):123–139

    Article  CAS  PubMed  Google Scholar 

  9. Esmaeili-Mahani S, Satarian L (2015) Changes in regulator of G protein signaling-4 gene expression in the spinal cord of adrenalectomized rats in response to intrathecal morphine. Physiol Pharmacol 19(1):38–45

    Google Scholar 

  10. Jin J, Kittanakom S, Wong V, Reyes BA, Van Bockstaele EJ, Stagljar I, Berrettini W, Levenson R (2010) Interaction of the mu-opioid receptor with GPR177 (Wntless) inhibits Wnt secretion: potential implications for opioid dependence. BMC Neurosci 11:33

    Article  PubMed  PubMed Central  Google Scholar 

  11. Borlongan CV, Hayashi T, Oeltgen PR, Su T-P, Wang Y (2009) Hibernation-like state induced by an opioid peptide protects against experimental stroke. BMC Biol 7:31

    Article  PubMed  PubMed Central  Google Scholar 

  12. Al-Hasani R, Bruchas MR (2011) Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 115:1363

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Morshead CM, Craig CG, van der Kooy D (1998) In vivo clonal analyses reveal the properties of endogenous neural stem cell proliferation in the adult mammalian forebrain. Development 125:2251–2261

    CAS  PubMed  Google Scholar 

  14. Zhao C, Sun G, Li S, Lang M-F, Yang S, Li W, Shi Y (2010) MicroRNA let-7b regulates neural stem cell proliferation and differentiation by targeting nuclear receptor TLX signaling. Proc Natl Acad Sci USA 107:1876–1881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ma J, Yuan X, Qu H, Zhang J, Wang D, Sun X, Zheng Q (2015) The role of reactive oxygen species in morphine addiction of SH-SY5Y cells. Life Sci 124:128–135

    Article  CAS  PubMed  Google Scholar 

  16. Galea LA, Spritzer MD, Barker JM, Pawluski JL (2006) Gonadal hormone modulation of hippocampal neurogenesis in the adult. Hippocampus 16:225–232

    Article  CAS  PubMed  Google Scholar 

  17. Malinowska-Kolodziej I, Larysz-Brysz M, Jedrzejowska-Szypulka H, Marcol W, Wlaszczuk A, Lewin-Kowalik J (2008) 17beta-estradiol and predegenerated nerve graft effect on hippocampal neurogenesis in adult female rats. Neuro Endocrinol lett 30:195–203

    Google Scholar 

  18. Nguyen T-VV, Yao M, Pike CJ (2009) Dihydrotestosterone activates CREB signaling in cultured hippocampal neurons. Brain Res 1298:1–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu H, Jia D, Li A, Chau J, He D, Ruan X, Liu F, Li J, He L, Li B (2012) p53 regulates neural stem cell proliferation and differentiation via BMP-Smad1 signaling and Id1. Stem cells Dev 22:913–927

    Article  PubMed Central  Google Scholar 

  20. Shoae-Hassani A, Sharif S, Verdi J (2011) A 5α-reductase inhibitor, finasteride, increases differentiation and proliferation of embryonal carcinoma cell-derived-neural cells. Med Hypotheses 76(1):11–13

    Article  CAS  PubMed  Google Scholar 

  21. Pradeep P, Li X, Peegel H, Menon K (2002) Dihydrotestosterone inhibits granulosa cell proliferation by decreasing the cyclin D2 mRNA expression and cell cycle arrest at G1 phase. Endocrinology 143:2930–2935

    Article  CAS  PubMed  Google Scholar 

  22. Shoae-Hassani A, Sharif S, Tabatabaei SAM, Verdi J (2011) Could the endogenous opioid, morphine, prevent neural stem cell proliferation? Med Hypotheses 76:225–229

    Article  CAS  PubMed  Google Scholar 

  23. Sharif A, Shoae-Hassani A, Sharif S, Banafshe HR, Mortazavi-Tabatabaei SA, Verdi J (2013) 5α-reductase 1 regulates spinal cord testosterone after morphine administration. Neurol Sci 34:19–23

    Article  PubMed  Google Scholar 

  24. Goodman Y, Bruce AJ, Cheng B, Mattson MP (1996) Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid β-peptide toxicity in hippocampal neurons. J Neurochem 66:1836–1844

    Article  CAS  PubMed  Google Scholar 

  25. Maric D, Maric I, Chang YH, Barker JL (2003) Prospective cell sorting of embryonic rat neural stem cells and neuronal and glial progenitors reveals selective effects of basic fibroblast growth factor and epidermal growth factor on self-renewal and differentiation. J Neurosci 23:240–251

    CAS  PubMed  Google Scholar 

  26. Mohammad Hossein Geranmayeh AB, Barin A, Salar-Amoli J, Dehghan MM, Rahbarghazi R, Azari H (2015) Paracrine neuroprotective effects of neural stem cells on glutamate-induced cortical neuronal cell excitotoxicity. Adv Pharm Bull. doi:10.15171/apb.2015.070

    PubMed  PubMed Central  Google Scholar 

  27. Girard SD, Devéze A, Nivet E, Gepner B, Roman FS, Féron F (2011) Isolating nasal olfactory stem cells from rodents or humans. J Vis Exp 54 pii: 2762

  28. Ghods AJ, Irvin D, Liu G, Yuan X, Abdulkadir IR, Tunici P, Konda B, Wachsmann-Hogiu S, Black KL, Yu JS (2007) Spheres isolated from 9L gliosarcoma rat cell line possess chemoresistant and aggressive cancer stem-like cells. Stem Cells 25:1645–1653

    Article  CAS  PubMed  Google Scholar 

  29. Rahbarghazi R, Nassiri SM, Khazraiinia P, Kajbafzadeh A-M, Ahmadi SH, Mohammadi E, Molazem M, Zamani-Ahmadmahmudi M (2012) Juxtacrine and paracrine interactions of rat marrow-derived mesenchymal stem cells, muscle-derived satellite cells, and neonatal cardiomyocytes with endothelial cells in angiogenesis dynamics. Stem Cells Dev 22:855–865

    Article  PubMed  PubMed Central  Google Scholar 

  30. Willner D, Cohen-Yeshurun A, Avidan A, Ozersky V, Shohami E, Leker RR (2014) Short term morphine exposure in vitro alters proliferation and differentiation of neural progenitor cells and promotes apoptosis via mu receptors. PLoS One 9(7):e103043

    Article  PubMed  PubMed Central  Google Scholar 

  31. Whittington M, Traub R, Faulkner H, Jefferys J, Chettiar K (1998) Morphine disrupts long-range synchrony of gamma oscillations in hippocampal slices. Proc Natl Acad Sci USA 95:5807–5811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Saboory E, Derchansky M, Ismaili M, Jahromi SS, Brull R, Carlen PL, El Beheiry H (2007) Mechanisms of morphine enhancement of spontaneous seizure activity. Anesth Analg 105:1729–1735

    Article  CAS  PubMed  Google Scholar 

  33. Lewis SS, Loram LC, Hutchinson MR, Li C-M, Zhang Y, Maier SF, Huang Y, Rice KC, Watkins LR (2012) (+)-naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats. J Pain 13:498–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Feng X, Ippolito GC, Tian L, Wiehagen K, Oh S, Sambandam A, Willen J, Bunte RM, Maika SD, Harriss JV (2010) Foxp1 is an essential transcriptional regulator for the generation of quiescent naive T cells during thymocyte development. Blood 115:510–518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Challen GA, Boles N, Lin KYK, Goodell MA (2009) Mouse hematopoietic stem cell identification and analysis. Cytometry A 75:14–24

    Article  PubMed  PubMed Central  Google Scholar 

  36. Arguello AA, Harburg GC, Schonborn JR, Mandyam CD, Yamaguchi M, Eisch AJ (2008) Time course of morphine’s effects on adult hippocampal subgranular zone reveals preferential inhibition of cells in S phase of the cell cycle and a subpopulation of immature neurons. Neuroscience 157:70–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ha JS, Lee C-S, Maeng J-S, Kwon K-S, Park SS (2009) Chronic glutamate toxicity in mouse cortical neuron culture. Brain Res 1273:138–143

    Article  CAS  PubMed  Google Scholar 

  38. Sahebgharani M, Nejati M, Sepehrizadeh Z, Khorramizadeh M-R, Bahrololoumi-Shapourabadi M, Hashemi-Bozchlou S, Esmaeili J, Ghazi-Khansari M (2008) Lithium chloride protects PC12 pheochromocytoma cell line from morphine-induced apoptosis. Arch Iran Med 11:639–648

    CAS  PubMed  Google Scholar 

  39. Boronat MA, García-Fuster MJ, García-Sevilla JA (2001) Chronic morphine induces up-regulation of the pro-apoptotic Fas receptor and down-regulation of the anti-apoptotic Bcl-2 oncoprotein in rat brain. Br J Pharmacol 134:1263–1270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tegeder I, Grösch S, Schmidtko A, Häussler A, Schmidt H, Niederberger E, Scholich K, Geisslinger G (2003) G protein-independent G1 cell cycle block and apoptosis with morphine in adenocarcinoma cells: involvement of p53 phosphorylation. Cancer Res 63:1846–1852

    CAS  PubMed  Google Scholar 

  41. Gupta K, Kshirsagar S, Chang L, Schwartz R, Law P-Y, Yee D, Hebbel RP (2002) Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res 62:4491–4498

    CAS  PubMed  Google Scholar 

  42. Gan TJ, Ginsberg B, Glass P, Fortney J, Jhaveri R, Perno R (1997) Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate. Anesthesiology 87:1075–1081

    Article  CAS  PubMed  Google Scholar 

  43. Wang Q, Zhou H, Gao H, Chen S-H, Chu C-H, Wilson B, Hong J-S (2012) Naloxone inhibits immune cell function by suppressing superoxide production through a direct interaction with gp91phox subunit of NADPH oxidase. J Neuroinflammation 9:32

    Article  PubMed  PubMed Central  Google Scholar 

  44. Wang H-Y, Friedman E, Olmstead M, Burns L (2005) Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in mu opioid receptor–G protein coupling and Gβγ signaling. Neuroscience 135:247–261

    Article  CAS  PubMed  Google Scholar 

  45. Cui J, Wang Y, Dong Q, Wu S, Xiao X, Hu J, Chai Z, Zhang Y (2011) Morphine protects against intracellular amyloid toxicity by inducing estradiol release and upregulation of Hsp70. J Neurosci 31:16227–16240

    Article  CAS  PubMed  Google Scholar 

  46. Ghiafeh Davoodi F, Javan M, Ahmadiani A (2010) The effect of swim stress on morphine tolerance development and the possible role of nitric oxide in this process. Iran J Pharm Res 4:167–173

    Google Scholar 

  47. Vuong C, Van Uum SH, O’Dell LE, Lutfy K, Friedman TC (2010) The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev 31:98–132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mensah-Nyagan AG, Do-Rego JL, Feuilloley M, Marcual A, Lange C, Pelletier G, Vaudry H (1996) In vivo and in vitro evidence for the biosynthesis of testosterone in the telencephalon of the female frog. J Neurochem 67:413–422

    Article  CAS  PubMed  Google Scholar 

  49. Spritzer MD, Galea LA (2007) Testosterone and dihydrotestosterone, but not estradiol, enhance survival of new hippocampal neurons in adult male rats. Dev Neurobiol 67:1321–1333

    Article  CAS  PubMed  Google Scholar 

  50. Estrada M, Varshney A, Ehrlich BE (2006) Elevated testosterone induces apoptosis in neuronal cells. J Biol Chem 281:25492–25501

    Article  CAS  PubMed  Google Scholar 

  51. Singer CA, Rogers KL, Strickland TM, Dorsa DM (1996) Estrogen protects primary cortical neurons from glutamate toxicity. Neurosci Lett 212:13–16

    Article  CAS  PubMed  Google Scholar 

  52. Chabab A, Sultan C, Fenart O, Descomps B (1986) Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts. J Steroid Biochem 25:165–169

    Article  CAS  PubMed  Google Scholar 

  53. Bethea CL, Reddy AP, Robertson N, Coleman K (2013) Effects of aromatase inhibition and androgen activity on serotonin and behavior in male macaques. Behav Neurosci 127:400–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Marić D, Stojilković S, Krsmanović L, Simonović I, Kovačević R, Andjus R (1987) Rapid naloxone-induced alterations of androgen variables in the growing male rat. Neuroendocrinology 46:167–175

    Article  PubMed  Google Scholar 

  55. Matthes HW, Maldonado R, Simonin F, Valverde O, Slowe S, Kitchen I, Befort K, Dierich A, Le Meur M, Dollé P (1996) Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the µ-opioid-receptor gene. Nature 383(6603):819–823

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Navid Feizy, Alireza Nourazarian & Nima Abdyazdani

  2. Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Navid Feizy, Alireza Nourazarian, Reza Rahbarghazi, Hojjatollah Nozad Charoudeh & Soheila Montazersaheb

  3. Department of Medical Education, Medical Education Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Mohamadreza Narimani

Authors
  1. Navid Feizy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alireza Nourazarian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Reza Rahbarghazi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hojjatollah Nozad Charoudeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nima Abdyazdani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Soheila Montazersaheb
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mohamadreza Narimani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alireza Nourazarian.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Feizy, N., Nourazarian, A., Rahbarghazi, R. et al. Morphine Inhibited the Rat Neural Stem Cell Proliferation Rate by Increasing Neuro Steroid Genesis. Neurochem Res 41, 1410–1419 (2016). https://doi.org/10.1007/s11064-016-1847-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-016-1847-7

Keywords

Search

Navigation