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Neonatal Morphine Administration Leads to Changes in Hippocampal BDNF Levels and Antioxidant Enzyme Activity in the Adult Life of Rats

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Abstract

It is know that repeated exposure to opiates impairs spatial learning and memory and that the hippocampus has important neuromodulatory effects after drug exposure and withdrawal symptoms. Thus, the aim of this investigation was to assess hippocampal levels of BDNF, oxidative stress markers associated with cell viability, and TNF-α in the short, medium and long term after repeated morphine treatment in early life. Newborn male Wistar rats received subcutaneous injections of morphine (morphine group) or saline (control group), 5 μg in the mid-scapular area, starting on postnatal day 8 (P8), once daily for 7 days, and neurochemical parameters were assessed in the hippocampus on postnatal days 16 (P16), 30 (P30), and 60 (P60). For the first time, we observed that morphine treatment in early life modulates BDNF levels in the medium and long term and also modulates superoxide dismutase activity in the long term. In addition, it was observed effect of treatment and age in TNF-α levels, and no effects in lactate dehydrogenase levels, or cell viability. These findings show that repeated morphine treatment in the neonatal period can lead to long-lasting neurochemical changes in the hippocampus of male rats, and indicate the importance of cellular and intracellular adaptations in the hippocampus after early-life opioid exposure to tolerance, withdrawal and addiction.

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Abbreviations

BDNF:

Brain-derived neurotrophic factor

DCF:

Dichlorofluorescein

DCFH:

Dichlorodihydrofluorescein

DMSO:

Dimethyl sulfoxide

DTNB:

5,5’-Dithiobis(2-nitrobenzoic acid)

EDTA:

Ethylenediaminetetraacetic acid

ELISA:

Enzyme-linked immunosorbent assay

GPx:

Glutathione peroxidase

HEPES:

2-[4-(2-Hydroxyethyl)piperazin-1-yl]ethanesulfonic acid

INT:

2-(4-Iodophenyl)-3-(4-nitrophenol)-5-phenyltetrazolium chloride

LDH:

Lactate dehydrogenase

MTT:

3(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NADPH:

Nicotinamide adenine dinucleotide phosphate, reduced form

PBS:

Phosphate buffered saline

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

SNK:

Student–Newman–Keuls test

SOD:

Superoxide dismutase

TMB:

3,3′,5,5′-Tetramethylbenzidine

TNB:

2-Nitro-5-thiobenzoic acid

TNF-α:

Tumour necrosis factor alpha

TrkB:

Tyrosine kinase B receptor

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Acknowledgments

This study was supported by the Brazilian National Council for Scientific and Technological Development—CNPq (I.L.S. Torres, W. Caumo, I.R. Siqueira, C. Dalmaz); the National Coordination for the Development of Higher Education Personnel—CAPES (J.R. Rozisky, G. Laste, I.C. de Macedo) Graduate Research Group (GPPG) of Hospital de Clínicas de Porto Alegre (I.L.S. Torres—Grant 08345) and FAPERGS/CNPq (PRONEM-003/2011).

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Authors and Affiliations

  1. Pain Pharmacology and Neuromodulation Laboratory: Animal Models, Department of Pharmacology, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), Rua Sarmento Leite, 500 sala 202, Porto Alegre, RS, 90050-170, Brazil

    J. R. Rozisky, G. Laste, I. C. de Macedo, V. S. Santos, I. C. C. de Souza, W. Caumo & I. L. S. Torres

  2. Postgraduate Program in Medical Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil

    J. R. Rozisky, G. Laste, I. C. C. de Souza, W. Caumo & I. L. S. Torres

  3. Neuropsychopharmacology Laboratory, Department of Pharmacology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil

    C. Vanzella, K. Bertoldi, G. A. Lovatel & I. R. Siqueira

  4. Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil

    R. Krolow, C. Noschang, C. Vanzella & C. Dalmaz

  5. Animal Experimentation Unit, Graduate Research Group, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

    J. R. Rozisky, G. Laste, I. C. de Macedo, V. S. Santos, I. C. C. de Souza, W. Caumo & I. L. S. Torres

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  1. J. R. Rozisky
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  2. G. Laste
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  3. I. C. de Macedo
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  4. V. S. Santos
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  10. I. C. C. de Souza
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  11. I. R. Siqueira
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  14. I. L. S. Torres
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Correspondence to I. L. S. Torres.

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Rozisky, J.R., Laste, G., de Macedo, I.C. et al. Neonatal Morphine Administration Leads to Changes in Hippocampal BDNF Levels and Antioxidant Enzyme Activity in the Adult Life of Rats. Neurochem Res 38, 494–503 (2013). https://doi.org/10.1007/s11064-012-0941-8

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  • DOI: https://doi.org/10.1007/s11064-012-0941-8

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