Neurotoxicity Research

, Volume 19, Issue 4, pp 649–659 | Cite as

Minocycline Prevents Morphine-Induced Apoptosis in Rat Cerebral Cortex and Lumbar Spinal Cord: A Possible Mechanism for Attenuating Morphine Tolerance

  • Kambiz Hassanzadeh
  • Bohlool Habibi-asl
  • Safar Farajnia
  • Leila Roshangar
Article

Abstract

Tolerance to the chronic administration of opioids such as morphine reduces the utility of these drugs in pain management. Despite significant investigation, the precise cellular mechanisms underlying opioid tolerance and dependence remain elusive. It has been indicated that tolerance to the analgesic effect of morphine is associated with apoptosis in the central nervous system. The aim of this study was to examine the effects of the intracerebroventricular (icv) administration of minocycline (a second-generation tetracycline) on morphine-induced apoptosis in the cerebral cortex and lumbar spinal cord of rats after morphine-induced tolerance. Different groups of rats received either morphine (ip) and distilled water (icv) or morphine and different doses of minocycline (icv) or minocycline alone once per day. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) method was used to analyze apoptosis. The anti-apoptotic factors, Bcl-2 and HSP 70 and the pro-apoptotic element caspase-3 were evaluated by immunoblotting. The results indicated that minocycline attenuated the number of apoptotic cells in both the cerebral cortex and lumbar spinal cord. Immunoblotting findings showed that the amounts of anti-apoptotic agents (Bcl-2 and HSP 70) were greater in the treatment groups than in the controls in both regions. Although minocycline did not change the level of caspase-3 at the doses used with morphine but the minocycline treated rats showed a significantly lower increase in caspase-3 activity than did in the control. In conclusion, minocycline decreased the number of TUNEL-positive cells and increased the amount of anti-apoptotic factors (Bcl-2 and HSP 70), but did not change the caspase-3 content.

Keywords

Apoptosis Intracerebroventricular Minocycline Morphine Tolerance 

References

  1. Bellmann K, Jaattela M, Wissing D, Burkart V, Kolb H (1996) Heat shock protein hsp70 overexpression confers resistance against nitric oxide. FEBS Lett 391:185–188PubMedCrossRefGoogle Scholar
  2. Boronat MA, Garcia-Fuster MJ, Garcia-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 134:1263–1270PubMedCrossRefGoogle Scholar
  3. Chen Q, Cui J, Zhang Y, Yu LC (2008) Prolonged morphine application modulates Bax and Hsp70 levels in primary rat neurons. Neurosci Lett 441:311–314PubMedCrossRefGoogle Scholar
  4. Cho KO, La HO, Cho YJ, Sung KW, Kim SY (2006) Minocycline attenuates white matter damage in a rat model of chronic cerebral hypoperfusion. J Neurosci Res 83:285–291PubMedCrossRefGoogle Scholar
  5. Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Kim HS, Park CH, Jeong YH, Yoo J, Lee JP, Chang KA, Kim S, Suh YH (2007) Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer’s disease models. Neuropsychopharmacology 32:2393–2404PubMedCrossRefGoogle Scholar
  6. Domercq M, Matute C (2004) Neuroprotection by tetracyclines. Trends Pharmacol Sci 25:609–612PubMedCrossRefGoogle Scholar
  7. Gonzalez JC, Egea J, Del Carmen Godino M, Fernandez-Gomez FJ, Sanchez-Prieto J, Gandia L, Garcia AG, Jordan J, Hernandez-Guijo JM (2007) Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca(2+) signalling in hippocampal neurons. Eur J Neurosci 26:2481–2495PubMedCrossRefGoogle Scholar
  8. Gordon SA, Hoffman RA, Simmons RL, Ford HR (1997) Induction of heat shock protein 70 protects thymocytes against radiation-induced apoptosis. Arch Surg 132:1277–1282PubMedGoogle Scholar
  9. Habibi-Asl B, Alimohammadi B, Charkhpour M, Hassanzadeh K (2009a) Evaluation the effects of systemic administration of minocycline and riluzole on tolerance to morphine analgesic effect in rat. Pharm Sci (J Fac Pharm, Tabriz Univ Med Sci) 15:205–212Google Scholar
  10. Habibi-Asl B, Hassanzadeh K, Charkhpour M (2009b) Central administration of minocycline and riluzole prevents morphine-induced tolerance in rats. Anesth Analg 109:936–942PubMedCrossRefGoogle Scholar
  11. Hassanzadeh K, Habibi-asl B, Roshangar L, Nemati M, Ansarin M, Farajnia S (2010) Intracerebroventricular administration of riluzole prevents morphine-induced apoptosis in the rat lumbar spinal cord. Pharmacol Rep 62(4):664–673PubMedGoogle Scholar
  12. Heo K, Cho YJ, Cho KJ, Kim HW, Kim HJ, Shin HY, Lee BI, Kim GW (2006) Minocycline inhibits caspase-dependent and -independent cell death pathways and is neuroprotective against hippocampal damage after treatment with kainic acid in mice. Neurosci Lett 398:195–200PubMedCrossRefGoogle Scholar
  13. Inturrisi CE (1997) Preclinical evidence for a role of glutamatergic systems in opioid tolerance and dependence. Semin Neurosci 9:110–119CrossRefGoogle Scholar
  14. Johnston IN, Milligan ED, Wieseler-Frank J, Frank MG, Zapata V, Campisi J, Langer S, Martin D, Green P, Fleshner M, Leinwand L, Maier SF, Watkins LR (2004) A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci 24:7353–7565PubMedCrossRefGoogle Scholar
  15. Kraus RL, Pasieczny R, Lariosa-Willingham K, Turner MS, Jiang A, Trauger JW (2005) Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-scavenging activity. J Neurochem 94:819–827PubMedCrossRefGoogle Scholar
  16. Li CY, Lee JS, Ko YG, Kim JI, Seo JS (2000) Heat shock protein 70 inhibits apoptosis downstream of cytochrome c release and upstream of caspase-3 activation. J Biol Chem 275:25665–25671PubMedCrossRefGoogle Scholar
  17. Mao J (1999) NMDA and opioid receptors: their interactions in antinociception, tolerance and neuroplasticity. Brain Res Brain Res Rev 30:289–304PubMedCrossRefGoogle Scholar
  18. Mao J, Price DD, Zhu J, Lu J, Mayer DJ (1997) The inhibition of nitric oxide-activated poly(ADP-ribose) synthetase attenuates transsynaptic alteration of spinal cord dorsal horn neurons and neuropathic pain in the rat. Pain 72:355–366PubMedCrossRefGoogle Scholar
  19. Mao J, Sung B, Ji RR, Lim G (2002) Neuronal apoptosis associated with morphine tolerance: evidence for an opioid-induced neurotoxic mechanism. J Neurosci 22:7650–7661PubMedGoogle Scholar
  20. Mika J, Wawrzczak-Bargiela A, Osikowicz M, Makuch W, Przewlocka B (2009) Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice. Brain Behav Immun 23:75–84PubMedCrossRefGoogle Scholar
  21. Morimoto N, Shimazawa M, Yamashima T, Nagai H, Hara H (2005) Minocycline inhibits oxidative stress and decreases in vitro and in vivo ischemic neuronal damage. Brain Res 1044:8–15PubMedCrossRefGoogle Scholar
  22. Mosser DD, Caron AW, Bourget L, Denis-Larose C, Massie B (1997) Role of the human heat shock protein hsp70 in protection against stress-induced apoptosis. Mol Cell Biol 17:5317–5327PubMedGoogle Scholar
  23. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic Press, LondonGoogle Scholar
  24. Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID (2002) Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol 51:215–223PubMedCrossRefGoogle Scholar
  25. Rothman SM, Olney JW (1986) Glutamate and the pathophysiology of hypoxic—ischemic brain damage. Ann Neurol 19:105–111PubMedCrossRefGoogle Scholar
  26. Sadowski T, Steinmeyer J (2001) Minocycline inhibits the production of inducible nitric oxide synthase in articular chondrocytes. J Rheumatol 28:336–340PubMedGoogle Scholar
  27. Salinska E, Danysz W, Lazarewicz JW (2005) The role of excitotoxicity in neurodegeneration. Folia Neuropathol 43:322–339PubMedGoogle Scholar
  28. Sanchez Mejia RO, Ona VO, Li M, Friedlander RM (2001) Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. Neurosurgery 48:1393–1399 (discussion 1399–1401)PubMedCrossRefGoogle Scholar
  29. Singhal PC, Sharma P, Kapasi AA, Reddy K, Franki N, Gibbons N (1998) Morphine enhances macrophage apoptosis. J Immunol 160:1886–1893PubMedGoogle Scholar
  30. Singhal PC, Kapasi AA, Reddy K, Franki N, Gibbons N, Ding G (1999) Morphine promotes apoptosis in Jurkat cells. J Leukoc Biol 66:650–658PubMedGoogle Scholar
  31. Stirling DP, Khodarahmi K, Liu J, McPhail LT, McBride CB, Steeves JD, Ramer MS, Tetzlaff W (2004) Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury. J Neurosci 24:2182–2190PubMedCrossRefGoogle Scholar
  32. Stirling DP, Koochesfahani KM, Steeves JD, Tetzlaff W (2005) Minocycline as a neuroprotective agent. Neuroscientist 11:308–322PubMedCrossRefGoogle Scholar
  33. Tikka TM, Koistinaho JE (2001) Minocycline provides neuroprotection against N-methyl-d-aspartate neurotoxicity by inhibiting microglia. J Immunol 166:7527–7533PubMedGoogle Scholar
  34. Wang X, Zhu S, Drozda M, Zhang W, Stavrovskaya IG, Cattaneo E, Ferrante RJ, Kristal BS, Friedlander RM (2003) Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington’s disease. Proc Natl Acad Sci USA 100:10483–10487PubMedCrossRefGoogle Scholar
  35. Whiteside GT, Munglani R (2001) Cell death in the superficial dorsal horn in a model of neuropathic pain. J Neurosci Res 64:168–173PubMedCrossRefGoogle Scholar
  36. Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, Choi DK, Ischiropoulos H, Przedborski S (2002) Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 22:1763–1771PubMedGoogle Scholar
  37. Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J (1999) A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 96:13496–13500PubMedCrossRefGoogle Scholar
  38. Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, Sarang S, Liu AS, Hartley DM, Wu DC, Gullans S, Ferrante RJ, Przedborski S et al (2002) Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417:74–78PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Kambiz Hassanzadeh
    • 1
    • 2
  • Bohlool Habibi-asl
    • 2
  • Safar Farajnia
    • 3
    • 4
  • Leila Roshangar
    • 5
  1. 1.Department of Physiology and Pharmacology, Faculty of MedicineKurdistan University of Medical SciencesSanandajIran
  2. 2.Department of Pharmacology and Toxicology, Faculty of PharmacyTabriz University of Medical SciencesTabrizIran
  3. 3.Biotechnology Research CenterTabriz University of Medical SciencesTabrizIran
  4. 4.Drug Applied Research CenterTabriz University of Medical SciencesTabrizIran
  5. 5.Department of Anatomy and Histology, Faculty of MedicineTabriz University of Medical SciencesTabrizIran

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