Regulation of Pleiotrophin, Midkine, Receptor Protein Tyrosine Phosphatase β/ζ, and Their Intracellular Signaling Cascades in the Nucleus Accumbens During Opiate Administration

• Published in: The international journal of neuropsychopharmacology 2016-01, Vol.19 (1), p.pyv077
• Main Authors: García-Pérez, Daniel, Laorden, María Luisa, Milanés, María Victoria
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - pharmacology; Analysis of Variance; Animals; Astrocytes - drug effects; Astrocytes - metabolism; Carrier Proteins - metabolism; Cytokines - metabolism; Glial Fibrillary Acidic Protein - metabolism; Midkine; Morphine - pharmacology; Naloxone - pharmacology; Narcotic Antagonists - pharmacology; Neurons - drug effects; Neurons - metabolism; Nucleus Accumbens - drug effects; Rats; Rats, Wistar; Receptor-Like Protein Tyrosine Phosphatases, Class 5 - metabolism; Signal Transduction - drug effects; Time Factors
• ISSN: 1461-1457; 1469-5111
• DOI: 10.1093/ijnp/pyv077

Background: Most classes of addictive substances alter the function and structural plasticity of the brain reward circuitry. Midkine (MK) and pleiotrophin (PTN) are growth/differentiation cytokines which, similarly to neurotrophins, play an important role in repair, neurite outgrowth, and cell differentiation. PTN or MK signaling through receptor protein tyrosine phosphatase β/ζ (RPTPβ/ζ), leads to the activation of extracellular signal-regulated kinases and thymoma viral proto-oncogene. This activation induces morphological changes and modulates 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. Methods: In the present work we studied the effect of acute morphine administration, chronic morphine administration, and morphine withdrawal on PTN, MK, and RPTPβ/ζ expression and on their signaling pathways in the nucleus accumbens. Results: 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 up-regulated 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 dopaminoceptive neurons expressed RPTPβ/ζ. Conclusions: All these observations suggest that the neurotrophic and behavioral adaptations that occur during opiate addiction could be, at least partly, mediated by cytokines.