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

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.

Dorsal hippocampal interleukin-1 signaling mediates heroin withdrawal-enhanced fear learning

“…The present work focused on the DH, a region in the brain known to be involved in memory. However, further studies should investigate whether IL-1β expression in other brain regions involved in opioid abuse, such as the ventral tegmental area and locus coeruleus, which regulate symptoms of opiate dependence and withdrawal (Garcia-Perez et al 2017;Kaufling and Aston-Jones 2015), may also contribute to HW-EFL and alter heroin withdrawal-induced weight changes.…”

Prefrontal Cortex Response to Prenatal Insult and Postnatal Opioid Exposure

“…Among genes in the cell adhesion molecules pathway impacted by morphine, PTPRC was under-expressed in morphine-treated pigs. Similarly, the tyrosine phosphatase receptor type Z ( PTPRZ1 ) was downregulated by chronic morphine treatment and upregulated after acute treatment in rodents [ 56 ]. Gene CDH1 participates in neurogenesis and cortical development and was under-expressed in the morphine-treated relative to the saline group ( Table 2 ).…”

Neuronal apoptosis induced by morphine withdrawal is mediated by the p75 neurotrophin receptor

“…Because opioid abusers undergo intermittent periods of withdrawal, impaired cognitive capabilities can be brought about withdrawal‐mediated impaired hippocampal function. It has been proposed that opioid withdrawal activates glial cells to release pro‐inflammatory cytokines (Garcia‐Perez et al., 2017; Hutchinson et al., 2009), including IL‐1β and TNFα, in several brain areas (Campbell et al., 2013). When pro‐inflammatory cytokines are released, they may cause brain damage (Colonna & Butovsky, 2017).…”

“…Several reports have shown that chronic use of opioid drugs have a negative impact on cognition (Welsch et al, 2020). Perez et al, 2017;Hutchinson et al, 2009), including IL-1β and TNFα, in several brain areas (Campbell et al, 2013). When pro-inflammatory cytokines are released, they may cause brain damage (Colonna & Butovsky, 2017).…”