Journal article
Morphine Increases Brain Levels of Ferritin Heavy Chain Leading to Inhibition of CXCR4-Mediated Survival Signaling in Neurons
The Journal of neuroscience, v 29(8), pp 2534-2544
25 Feb 2009
PMID: 19244528
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
This study focuses on the effect of μ-opioid receptor agonists on CXCR4 signaling in neurons and the mechanisms involved in regulation of neuronal CXCR4 by opiates. The data show that CXCR4 is negatively modulated by long-term morphine treatments both
in vitro
and
in vivo
; CXCR4 inhibition is caused by direct stimulation of μ-opioid receptors in neurons, leading to alterations of ligand-induced CXCR4 phosphorylation and upregulation of protein ferritin heavy chain (FHC), a negative intracellular regulator of CXCR4. Reduced coupling of CXCR4 to G-proteins was found in the brain of morphine-treated rats, primarily cortex and hippocampus. CXCR4-induced Gα
i
/Gβγ activities were suppressed after 24 h treatment of cortical neurons with morphine or the selective μ-opioid agonist DAMGO (
d
-Ala2-
N
-Me-Phe
4
-glycol
5
-enkephalin), as shown by analysis of downstream targets of CXCR4 (i.e., cAMP, Akt, and ERK1/2). These agonists also prevented CXCL12-induced phosphorylation of CXCR4, indicating a deficit of CXCR4 activation in these conditions. Indeed, morphine (or DAMGO) inhibited prosurvival signaling in neurons. These effects are not attributable to a reduction in CXCR4 expression or surface levels but rather to upregulation of FHC by opioids. The crucial role of FHC in inhibition of neuronal CXCR4 was confirmed by
in vitro
and
in vivo
RNA interference studies. Overall, these findings suggest that opiates interfere with normal CXCR4 function in the brain. By this mechanism, opiates could reduce the neuroprotective functions of CXCR4 and exacerbate neuropathology in opiate abusers who are affected by neuroinflammatory/infectious disorders, including neuroAIDS.
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Details
- Title
- Morphine Increases Brain Levels of Ferritin Heavy Chain Leading to Inhibition of CXCR4-Mediated Survival Signaling in Neurons
- Creators
- Rajarshi Sengupta - Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102Silvia Burbassi - Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102Saori Shimizu - Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102Silvia Cappello - Department of Pathology, Columbia University Medical Center, New York, New York 10032, andRichard B Vallee - Department of Pathology, Columbia University Medical Center, New York, New York 10032, andJoshua B Rubin - Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110Olimpia Meucci - Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102
- Publication Details
- The Journal of neuroscience, v 29(8), pp 2534-2544
- Publisher
- Society for Neuroscience
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000263719600022
- Other Identifier
- 991014878025304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Neurosciences