Cellular and Molecular Neurobiology

, Volume 36, Issue 6, pp 839–849 | Cite as

Expression of BDNF and TrkB Phosphorylation in the Rat Frontal Cortex During Morphine Withdrawal are NO Dependent

  • Danil I. Peregud
  • Alexander A. Yakovlev
  • Mikhail Yu. Stepanichev
  • Mikhail V. Onufriev
  • Leonid F. Panchenko
  • Natalia V. Gulyaeva
Original Research


Nitric oxide (NO) mediates pharmacological effects of opiates including dependence and abstinence. Modulation of NO synthesis during the induction phase of morphine dependence affects manifestations of morphine withdrawal syndrome, though little is known about mechanisms underlying this phenomenon. Neurotrophic and growth factors are involved in neuronal adaptation during opiate dependence. NO-dependent modulation of morphine dependence may be mediated by changes in expression and activity of neurotrophic and/or growth factors in the brain. Here, we studied the effects of NO synthesis inhibition during the induction phase of morphine dependence on the expression of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and insulin-like growth factor 1 (IGF1) as well as their receptors in rat brain regions after spontaneous morphine withdrawal in dependent animals. Morphine dependence in rats was induced within 6 days by 12 injections of morphine in increasing doses (10–100 mg/kg), and NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME) (10 mg/kg) was given 1 h before each morphine injection. The expression of the BDNF, GDNF, NGF, IGF1, and their receptors in the frontal cortex, striatum, hippocampus, and midbrain was assessed 40 h after morphine withdrawal. L-NAME treatment during morphine intoxication resulted in an aggravation of the spontaneous morphine withdrawal severity. Morphine withdrawal was accompanied by upregulation of BDNF, IGF1, and their receptors TrkB and IGF1R, respectively, on the mRNA level in the frontal cortex, and only BDNF in hippocampus and midbrain. L-NAME administration during morphine intoxication decreased abstinence-induced upregulation of these mRNAs in the frontal cortex, hippocampus and midbrain. L-NAME prevented from abstinence-induced elevation of mature but not pro-form of BDNF polypeptide in the frontal cortex. While morphine abstinence did not affect TrkB protein levels as well as its phosphorylation status, inhibition of NO synthesis decreased levels of phosphorylated TrkB after withdrawal. Thus, NO signaling during induction of dependence may be involved in the mechanisms of BDNF expression and processing at abstinence, thereby affecting signaling through TrkB in the frontal cortex.


Nitric oxide BDNF Rat brain Morphine dependence 



The study was supported by Russian Foundation for Basic Research Grant #10-04-01403 and 13-04-01415. The authors thank Natalia Lazareva and Natalia Stepanicheva for a superb technical support.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Danil I. Peregud
    • 1
    • 2
  • Alexander A. Yakovlev
    • 2
  • Mikhail Yu. Stepanichev
    • 2
  • Mikhail V. Onufriev
    • 2
  • Leonid F. Panchenko
    • 1
    • 3
  • Natalia V. Gulyaeva
    • 2
  1. 1.Federal State Budgetary Institution “V. Serbsky Federal Medical Research Centre for Psychiatry and Drug Addiction”, of the Ministry of Health of the Russian FederationMoscowRussia
  2. 2.Institute of Higher Nervous Activity and NeurophysiologyRussian Academy of SciencesMoscowRussia
  3. 3.Institute of General Pathology and PathophysiologyRussian Academy of SciencesMoscowRussia

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