Nitric oxide synthase activity and the level of nitrates/nitrites in brain regions during spontaneous morphine withdrawal in rats

  • D. I. Peregud
  • M. V. Onufriev
  • A. A. Yakovlev
  • M. Yu. Stepanichev
  • N. A. Lazareva
  • T. V. Pavlova
  • L. F. Panchenko
  • N. V. Gulyaeva
Experimental Studies


Activity of nitric oxide synthase (NOS) and concentrations of nitrate/nitrites (NO x ) were measured in brain regions of rats during spontaneous morphine withdrawal, which was modeled in male Wistar rats. The animals were injected with the increasing intraperitoneal doses (10–100 mg/kg, twice a day) of morphine hydrochloride for 6 days. Thirty six hours after the last injection the severity of the spontaneous morphine withdrawal syndrome was determined by specific autonomic and locomotor indices The withdrawal was accompanied by the increase of both NOS activity and NO x levels in the midbrain and hippocampus, the decrease of these parameters in striatum and hypothalamus, and lack of changes in cerebral cortex and brain stem. In cerebellum NOS activity decreased whereas NO x concentrations remained unchanged. In the cerebral cortex, striatum, midbrain, and cerebellum activity of NOS and NO x concentrations correlated with the withdrawal syndrome severity and also with the specific signs of abstinence.

Key words

spontaneous morphine withdrawal nitric oxide nitric oxide synthase nitrate/nitrite concentration brain rats 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Petrovsky, B.V. (Ed.), Entsiklopedicheskii slovar’ meditsinskikh terminov [in Russian] (Encyclopedic Dictionary of Medical Terms), 1983, vol. 1, Sovetskaya Entsiklopediya, Moscow, p. 560.Google Scholar
  2. 2.
    Torres, G. and Horowitz, J.M., Psychosom. Med., 1999, vol. 61, pp. 630–650.PubMedGoogle Scholar
  3. 3.
    Williams, J.T., Christie, M.J., and Manzoni, O., Physiol. Rev., 2001, vol. 81, pp. 299–343.PubMedGoogle Scholar
  4. 4.
    Cami, J. and Farre, M., New Engl. J. Med., 2003, vol. 349, pp. 975–986.PubMedCrossRefGoogle Scholar
  5. 5.
    Nestler, E.J., Nat. Rev. Neurosci., 2001, vol. 2, pp. 119–128.PubMedCrossRefGoogle Scholar
  6. 6.
    Eisch, A.J., Barrot, M., Schad, C.A., et al., Proc. Natl. Acad. Sci. USA, 2000, vol. 97, pp. 7579–7584.PubMedCrossRefADSGoogle Scholar
  7. 7.
    Moncada, S., Palmer, R.M.J., and Higgs, E.A., Parmacol. Rev., 1991, vol. 43, pp. 109–142.Google Scholar
  8. 8.
    Esplugues, J.V., Br. J. Pharmacol., 2002, vol. 135, pp. 1079–1095.PubMedCrossRefGoogle Scholar
  9. 9.
    Sahraei, H., Poorheidari, G., et al., Pharmacol. Biochem. Behav., 2004, vol. 77, pp. 111–116.PubMedCrossRefGoogle Scholar
  10. 10.
    Pasternak, G.W., Kolesnikov, Y.A., and Babey, A.M., Neuropsychopharmacology, 1995, vol. 13, pp. 309–313.PubMedCrossRefGoogle Scholar
  11. 11.
    London, E.D., Kimes, A.S., and Vaupel, D.B., NIDARes. Monogr., 1995, vol. 147, pp. 170–181.Google Scholar
  12. 12.
    Dyuzen, I.V., Motavkin, P.A., and Shorin, V.V., Byul. Eksper. Biol. Med., 2001, vol. 132, pp. 354–357.Google Scholar
  13. 13.
    Cuellar, B., Fernandez, A.P., Lizasoain, I., et al., Psychopharmacology (Berl.), 2000, vol. 148, pp. 66–73.CrossRefGoogle Scholar
  14. 14.
    Cappendijk, S.L.T., Garrelds, I.M., and Dzoljic, M.R., Nitric Oxide and Nervous System. Laurentians Mountains. Montreal, 1994, Abstract 1-18.Google Scholar
  15. 15.
    Leza, J.C., Lizasoain, I., Cuellar, B., et al., Naunyn Schmiedebergs Arch. Pharmacol., 1996, vol. 353, pp. 349–354.PubMedCrossRefGoogle Scholar
  16. 16.
    Lizasoain, I., Leza, J.C., Lizasoain, I., et al., Eur. J. Pharmacol., 1996, vol. 299, pp. 41–45.PubMedCrossRefGoogle Scholar
  17. 17.
    Li, J., Li, X., Pei, G., and Qin, B.Y., Zhongguo Yao Li Xue Bao, 1999, vol. 20, pp. 375–380.PubMedGoogle Scholar
  18. 18.
    Kumar, S. and Bhargava, H.N., Gen. Pharmacol., 1997, vol. 29, pp. 223–227.PubMedGoogle Scholar
  19. 19.
    Babey, A.M., Kolesnikov, Y., Cheng, J., et al., Neuropharmacology, 1994, vol. 33, pp. 1463–1470.PubMedCrossRefGoogle Scholar
  20. 20.
    Rahman, S., Ali Khan, R., and Kumar, A., BMC Complement. Altern. Med., 2002, vol. 2, p. 6.PubMedCrossRefGoogle Scholar
  21. 21.
    Dum, J., Blasig, J., and Herz, A., Eur. J. Pharmacol., 1981, vol. 70, pp. 293–300.PubMedCrossRefGoogle Scholar
  22. 22.
    Blasig, J., Herz, A., Reinhold, K., and Zieglgansberger, S., Psychopharmacologia (Berl.), 1973, vol. 33, pp. 19–38.CrossRefGoogle Scholar
  23. 23.
    Misko, T.P., Schilling, R.J., Salvemini, D., et al., Anal. Biochem., 1993, vol. 214, pp. 11–16.PubMedCrossRefGoogle Scholar
  24. 24.
    Onufriev, M.V., Semenova, T.P., Kolaeva, S.G., et al., Neurokhimiya, 2002, vol. 19, pp. 264–268.Google Scholar
  25. 25.
    Yakovlev, A.A. and Gulyaeva, N.V., Biomed. Khim., 2004, vol. 50, pp. 390–397.Google Scholar
  26. 26.
    Kagan, V.E., Prilipko, L.L., Savov, V.M., et al., Biokhimiya, 1979, vol. 44, pp. 379–385.Google Scholar
  27. 27.
    Nishikimi, M., Rao, N.A., and Yagi, K., Biochem. Biophys. Res. Commun., 1972, vol. 46, pp. 849–855.PubMedCrossRefGoogle Scholar
  28. 28.
    Yakovlev, A.A., Onufriev, M.V., Stepanichev, M.Yu., et al., Neurokhimiya, 2001, vol. 18, pp. 41–43.Google Scholar
  29. 29.
    Bradford, M.M., Anal. Biochem., 1976, vol. 72, pp. 248–254.PubMedCrossRefGoogle Scholar
  30. 30.
    Konstantinopolsky, M.A., Pirozhkov, S.V., Solov’eva, A.G., Panchenko, L.F., and Barkov, N.K., Eksper. Klin. Farmakol., 1992, vol. 55, pp. 21–24.Google Scholar
  31. 31.
    Panchenko, L.F., Pirozhkov, S.V., and Solov’eva, A.G., Vopr. Narkol., 1995, vol. 2, pp. 32–36.Google Scholar
  32. 32.
    Boronat, M., Garcia-Fuster, M.J., and Garcia-Sevilla, J.A., Br. J. Pharmacol., 2001, vol. 134, pp. 1263–1270.PubMedCrossRefGoogle Scholar
  33. 33.
    Turski, W.A., Czuczwar, S.J., Kleinrok, Z., and Turski, L., Life Sci., 1983, vol. 33, pp. 397–400.PubMedCrossRefGoogle Scholar
  34. 34.
    Panchenko, L.F., Peregud, D.I., Yakovlev, A.A., et al., Biomed. Khim., 2004, vol. 50, pp. 460–470.Google Scholar
  35. 35.
    Bhargava, H.N. and Cao, Y.J., Peptides, 1998, vol. 19, pp. 113–117.PubMedCrossRefGoogle Scholar
  36. 36.
    Golovko, A.I., Leontieva, L.V., Golovko, S.I., et al., Neurokhimiya, 2003, vol. 20, pp. 245–258.Google Scholar
  37. 37.
    Vaupel, D.B., Kimes, A.S., and London, E.D., Psychopharmacology (Berl.), 1995, vol. 118, pp. 361–368.CrossRefGoogle Scholar
  38. 38.
    Vaupel, D.B., Kimes, A.S., and London, E.D., Eur. J. Pharmacol., 1997, vol. 324, pp. 11–20.PubMedCrossRefGoogle Scholar
  39. 39.
    Ozek, M., Uresin, Y., and Gungor, M., Life Sci., 2003, vol. 72, pp. 1943–1951.PubMedCrossRefGoogle Scholar
  40. 40.
    Bredt, D.S. and Snyder, S.H., Annu. Rev. Biochem., 1994, vol. 63, pp. 175–195.PubMedCrossRefGoogle Scholar
  41. 41.
    Zhu, H., Brodsky, M., Gorman, A.L., and Inturrisi, C.E., Mol. Brain Res., 2003, vol. 114, pp. 154–162.PubMedCrossRefGoogle Scholar
  42. 42.
    Inoue, M., Mishina, M., and Ueda, H., J. Neurosci., 2003, vol. 23, pp. 6529–6536.PubMedGoogle Scholar
  43. 43.
    Mao, J., Brain Res. Rev., 1999, vol. 30, pp. 289–304.PubMedCrossRefGoogle Scholar
  44. 44.
    Nestler, E.J. and Aghajanian, G.K., Science, 1997, vol. 278, pp. 58–63.PubMedCrossRefGoogle Scholar
  45. 45.
    Ventayol, P., Busquets, X., and Garcia-Sevilla, J.A., Naunyn. Schmiedebergs Arch. Pharmacol., 1997, vol. 355, pp. 491–500.PubMedCrossRefGoogle Scholar
  46. 46.
    Bredt, D.S., Ferris, C.D., and Snyder, S.H., J. Biol. Chem., 1992, vol. 267, pp. 10976–10981.PubMedGoogle Scholar
  47. 47.
    Nakane, M., Mitchell, J., Forstermann, U., and Murad, F., Biochem. Biophys. Res. Commun., 1991, vol. 180, pp. 1396–1402.PubMedCrossRefGoogle Scholar
  48. 48.
    Liu, J.G. and Anand, K.J.S., Brain Res. Rev., 2001, vol. 38, pp. 1–19.PubMedCrossRefGoogle Scholar
  49. 49.
    Ohkuma, S. and Katsura, M., Prog. Neurobiol., 2001, vol. 64, pp. 97–108.PubMedCrossRefGoogle Scholar
  50. 50.
    Sullivan, M.E., Hall, S.R., Milne, T., and Jhamandas, K., Brain Res., 2000, vol. 859, pp. 45–56.PubMedCrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2007

Authors and Affiliations

  • D. I. Peregud
    • 1
  • M. V. Onufriev
    • 2
  • A. A. Yakovlev
    • 2
    • 3
  • M. Yu. Stepanichev
    • 2
  • N. A. Lazareva
    • 2
  • T. V. Pavlova
    • 2
  • L. F. Panchenko
    • 1
  • N. V. Gulyaeva
    • 2
  1. 1.National Scientific Center on AddictionMinistry of Healthcare of Russian FederationMoscowRussia
  2. 2.Institute of Higher Nervous Activity and NeurophysiologyRussian Academy of SciencesMoscowRussia
  3. 3.Moscow Institute of Physics and TechnologyDolgoprudnyi, Moscow regionRussia

Personalised recommendations