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Acute Morphine, Chronic Morphine, and Morphine Withdrawal Differently Affect Pleiotrophin, Midkine, and Receptor Protein Tyrosine Phosphatase β/ζ Regulation in the Ventral Tegmental Area

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Abstract

Pleiotrophin (PTN) and midkine (MK) are secreted growth factors and cytokines, proposed to be significant neuromodulators with multiple neuronal functions. PTN and MK are generally related with cell proliferation, growth, and differentiation by acting through different receptors. PTN or MK, signaling through receptor protein tyrosine phosphatase β/ζ (RPTPβ/ζ), lead to the activation of extracellular signal-regulated kinases (ERKs) and thymoma viral proto-oncogene (Akt), which induce morphological changes and modulate addictive behaviors. Besides, there is increasing evidence that during the development of drug addiction, astrocytes contribute to the synaptic plasticity by synthesizing and releasing substances such as cytokines. In the present work, we studied the effect of acute morphine, chronic morphine, and morphine withdrawal on PTN, MK, and RPTPβ/ζ expression and on their signaling pathways in the ventral tegmental area (VTA). Present results indicated that PTN, MK, and RPTPβ/ζ levels increased after acute morphine injection, returned to basal levels during chronic opioid treatment, and were upregulated again during morphine withdrawal. We also observed an activation of astrocytes after acute morphine injection and during opiate dependence and withdrawal. In addition, immunofluorescence analysis revealed that PTN, but not MK, was overexpressed in astrocytes and that dopaminergic neurons expressed RPTPβ/ζ. Interestingly, p-ERK 1/2 levels during chronic morphine and morphine withdrawal correlated RPTPβ/ζ expression. All these observations suggest that the neuroprotective and behavioral adaptations that occur during opiate addiction could be, at least partly, mediated by these cytokines.

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Abbreviations

PTN:

Pleiotrophin

MK:

Midkine

RPTPβ/ζ:

Receptor protein tyrosine phosphatase β/ζ

VTA:

Ventral tegmental area

GFAP:

Glial fibrillary acidic protein

GFAP-IR:

GFAP immunoreactivity

DA:

Dopamine

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Acknowledgments

This work was supported by grants from Ministerio de Ciencia e Innovación (SAF/FEDER 2009-07178; SAF/FEDER 2010-17907; SAF/FEDER 2013-49076-P), Spain; Red de Trastornos Adictivos, Spain; and Fundación Séneca (15405/PI/10) and Instituto Murciano de Investigación en Biomedicina (IMIB), Región de Murcia, Spain. Daniel García-Pérez was supported by a fellowship from Ministerio de Ciencia e Innovación (AP2009-2379).

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Authors and Affiliations

  1. Group of Cellular and Molecular Pharmacology, Department of Pharmacology, University of Murcia, Campus de Espinardo, 30100, Murcia, Spain

    Daniel García-Pérez, M. Luisa Laorden & M. Victoria Milanés

  2. IMIB, Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

    Daniel García-Pérez, M. Luisa Laorden & M. Victoria Milanés

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  1. Daniel García-Pérez
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  2. M. Luisa Laorden
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Correspondence to Daniel García-Pérez.

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The authors declare that they have no competing interests.

Authors’ Contribution

DG-P designed and performed the research, analyzed the data, and wrote the paper. MLL revised the manuscript. MVM conducted the astrocyte quantification and contributed to editing the paper.

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García-Pérez, D., Laorden, M.L. & Milanés, M.V. Acute Morphine, Chronic Morphine, and Morphine Withdrawal Differently Affect Pleiotrophin, Midkine, and Receptor Protein Tyrosine Phosphatase β/ζ Regulation in the Ventral Tegmental Area. Mol Neurobiol 54, 495–510 (2017). https://doi.org/10.1007/s12035-015-9631-2

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