Journal of neuroscience research
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Morphine differs from most opiates its poor ability to internalize μ opioid receptors (μORs). However, chronic treatment with morphine produces adaptational changes at the dynamin level, which enhance the efficiency of acute morphine stimulation to promote μOR internalization in enteric neurons. This study tested the effect of chronic treatment with fentanyl, a μOR-internalizing agonist, on ligand-induced endocytosis and the expression of the intracellular trafficking proteins, dynamin and β-arrestin, in enteric neurons using organotypic cultures of the guinea pig ileum. ⋯ Chronic fentanyl treatment did not alter dynamin or β-arrestin expression. These findings indicate that prolonged activation of μORs with an internalizing agonist such as fentanyl does not enhance the ability of acute morphine to trigger μOR endocytosis or induce changes in intracellular trafficking proteins, as observed with prolonged activation of μORs with a poorly internalizing agonist such as morphine. Cellular adaptations induced by chronic opiate treatment might be ligand dependent and vary with the agonist efficiency to induce receptor internalization.
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Spinal astrocytes have important mechanistic contributions to the initiation and maintenance of neurodegenerative diseases and chronic pain. Under inflammatory conditions, spinal astrocytes are exposed to cytokines such as tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), and these cytokines could alter astrocytic function by modulating connexin (Cx43), subunits that form channels that modulate intercellular communication in astrocytes. The current study investigated the alteration of Cx43-gap junction in rat primary cultured spinal astrocytes stimulated with cytokines by real-time PCR and Western blotting. ⋯ Both the decrease of Cx43 expression and the reduction in GJIC induced by the mixture of TNF-α and IFN-γ were prevented by blocking c-jun terminal kinase (JNK) but not by blocking extracellular signaling molecules ERK and p38 kinase, indicating a specific role of astrocytic JNK in the response to cytokines. In addition, treatment with cytokines potently induced the phosphorylation of JNK and c-jun in a time-dependent manner. These results indicate that intercellular communication of astrocytes is significantly disrupted in the inflammatory state and that stimulation of spinal astrocytes with inflammatory cytokines leads to significant inhibition of Cx43-GJIC through activation of the JNK signaling pathway.
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Peripheral injection with a high dose of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, into animals with mild or moderate spinal cord injury (SCI) for 1 week can reduce spinal cord tissue loss and promote hindlimb locomotor recovery. A purinergic adenosine triphosphate (ATP) receptor subtype, P2X4 receptor (P2X4 R), has been considered as a potential target to diminish SCI-associated inflammatory responses. In this study, using a minipump-based infusion system, we found that intraspinal infusion with VPA for 3 days into injured spinal cord significantly improved hindlimb locomotion of rats with severe SCI induced by a 10-g NYU impactor dropping from the height of 50 mm onto the spinal T9/10 segment. ⋯ Furthermore, in vitro study indicated that VPA, but not the other HDAC inhibitors, sodium butyrate and trichostatin A (TSA), caused downregulation of P2X4 R in microglia activated with lipopolysaccharide (LPS). Moreover, p38 mitogen-activated protein kinase (MAPK)-triggered signaling was involved in the effect of VPA on the inhibition of P2X4 R gene expression. In addition to the findings from others, our results also provide important evidence to show the inhibitory effect of VPA on P2X4 R expression in activated microglia, which may contribute to reduction of SCI-induced gliosis and subsequently preservation of spinal cord tissues. © 2013 Wiley Periodicals, Inc.
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Although many post-mortem studies have found evidence of central insulin resistance in Alzheimer's disease (AD) patients, results on changes of central insulin-like growth factor-1 (IGF-1) signaling in the pathological process of AD remain controversial. In the present study, we observed the activation states of IGF-1 downstream signaling in brain slices of transgenic mice carrying APPswe/PS1dE9 mutations (APP/PS1 mice) at both early and late stages (ex vivo) and further investigated the involvement of oligomeric β-amyloid (Aβ) and Aβ-enriched culture medium (CM) on IGF-1 sensitivity employing neuronal models (in vitro). ⋯ These observations indicate that the impaired central IGF-1 sensitivity at early and late stages of APP/PS1 transgenic mice might be attributable, at least partially, to the overproduced Aβ, especially the oligomeric Aβ. These findings may shed new light on the mechanisms underlying the defective IGF-1 signaling in AD pathogenesis and provide important clues for AD drug discovery.
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The financial and emotional cost of caring for children affected by hypoxic-ischemic encephalopathy (HIE) is enormous, and developing therapeutic strategies to prevent or ameliorate the severity of HI-related brain injury remains a major priority. In the past, supportive management was the mainstay of treatment, but considerable progress has been made in identifying and developing neuroprotective strategies for neonates with HIE. The neuroprotective effects of several therapeutic modalities, including anticonvulsants, hyperbaric oxygen, and erythropoietin, have been investigated. ⋯ The pathogenesis of HIE involves more than one pathway, and intervening in multiple pathways may yield better results than interventions targeted at a single cellular level. The therapeutic benefits of xenon and hypothermia have been confirmed in several in vitro and in vivo studies, both individually and in combination. With promising results being reported, it is, perhaps, only a matter of time before xenon and hypothermia become established as a standard care for neonates with HIE.