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Dissertation
Regulation of neuronal CXCR4 signaling by opioids
Doctor of Philosophy (Ph.D.), Drexel University
Mar 2009
DOI:
https://doi.org/10.17918/00008283
Abstract
Heterologous desensitization is a potential mechanism involved in the regulation of chemokine receptors. The chemokine CXCL12 and its receptor CXCR4, also a HIV co-receptor, play a significant role in neuronal development and homeostasis. Studies from our lab have shown that mu-opioid agonists, such as DAMGO and the endogenous peptide endomorphin-1 inhibit the neuroprotective action of CXCL12 in cultured rat cortical fleurons. Here we studied the cellular and molecular mechanisms behind opiate action and identified a novel mediator of the effect of opioids on CXCR4 signaling in vivo. Briefly, we show that the inhibitory action of opioids is due to a direct effect on neurons (i.e. flot glia-mediated) and requires prolonged mu-opioid receptor (MOR) stimulation. CXCR4-induced G[alpha]i and G[beta][gamma] activities are both suppressed following DAMGO treatment as indicated by analysis of different downstream targets regulated by CXCL12. GTP[gamma]S incorporation assays in brain suces also indicate a reduced coupling of CXCR4 to G[alpha]i in the cortex and hippocampus of morphine-treated rats. Furthermore, morphine pretreatment inhibits pro-survival signaling in cortical cultures. In addition, treatment of cultured neurons with morphine or DAMGO also leads to a decrease in the ligand-induced CXCR4 phosphorylation. Overall these findings point to a deficit of CXCR4 activation in opioid-treated neurons. Interestingly, initial studies with brain tissue samples from HIV and control patients show a reduction of CXCR4 phosphorylation (pS339) in HIV+ patients with neurological problems as compared to HIV- control and neurologically normal HIV+ individuals, suggesting that impairment in CXCR4 may lead to neuronal dysfunction in humans. Finally, we demonstrate for the first time the involvement of the ubiquitous peptide ferritin heavy chain (FHC) in mediating opioids' action on CXCR4 signaling. Treatment of cortical neurons with DAMGO or morphine up-regulates FHC levels through activation of MOR. Elevated FHC levels are also detected in cortical tissue from rats treated with morphine. The FHC increase temporarily correlates with the reduction of CXCR4-mediated responses while inhibition of FHC expression by siRNA prevents the effect of opioids on CXCR4. Altogether, these data suggest that opiates interfere with normal CXCR4 function in the brain and may exacerbate progression to neuroAIDS in HIV-positive drug users.
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Details
- Title
- Regulation of neuronal CXCR4 signaling by opioids
- Creators
- Rajarshi Sengupta
- Contributors
- Olimpia Meucci (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xvi, 183 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991021888967904721