Alterations of CXCR4 function in μ‐opioid receptor‐deficient glia

Abstract

The chemokine receptor CXCR4 and the μ-opioid receptor (MOR) are G-protein-coupled receptors (GPCRs) essential to normal function of the nervous and immune systems. Several studies suggest that MOR is a key regulator of CXCR4 in the brain; however, the molecular basis of the opioid/chemokine interaction are not fully understood and may involve different mechanisms in neuronal and glial cells. Our previous studies demonstrated that MOR stimulation specifically up-regulates the protein ferritin heavy chain (FHC) -an inhibitor of CXCR4 -in neurons and suggested additional mechanisms could be operative in glial cells. In this study, we investigated CXCR4 function in brains and astroglia cultures deprived of MOR. Reduced coupling of CXCR4 to G proteins was found in brain slices and tissue homogenates of MOR−/− mice compared to wild type (WT) controls. CXCR4-induced signaling was also reduced in glial cultures from MOR−/− mice, as shown by analysis of CXCR4 downstream targets (Akt and ERK1/2). Pharmacological studies with δ-opioid receptor (DOR)-specific ligands suggested that DOR-CXCR4 interactions are implicated in the inhibition of CXCR4 in MOR-deficient cells both in vitro and in vivo. Moreover, increased CXCR4/DOR co-immunoprecipitation was found in brain tissue and cultured glia from MOR−/− mice. Importantly, CXCR4 function was restored by pretreatment with a DOR antagonist. Overall, these findings indicate that DOR play a crucial role in the regulation of CXCR4 in glia, likely via silent receptor heterodimers. The data also suggest that the opiate system interferes with normal CXCR4 function in different ways and depending on receptor subtypes.

Glial cell activation in the spinal cord and dorsal root ganglia induced by surgery in mice

“…This could be related to the fact that neuronal and glial cells both express opioid receptors in cell membranes (Bokhari et al, 2009;Burbassi et al, 2010;Kao et al, 2012) that are able to bind the ( À ) but not the ( þ) isomers of endogenous and exogenous opioids (agonists or antagonists). ( þ) Naloxone cannot bind to neuronal opioid receptors, and does not induce hyperalgesia on day 21, but induced significant astrocyte re-activation in the spinal cord (Fig.…”

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

“…Astrocyte opioid receptor expression is by far the best defined, including expression of (Dobrenis et al, 1995;Hauser et al, 1996;Ruzicka et al, 1996;Festa et al, 2002;Burbassi et al, 2010), (Bunn et al, 1985;Gorodinsky et al, 1995;Maderspach et al, 1995), and ␦ receptors (Thorlin et al, 1998a). However, this opioid receptor expression is highly varied.…”

Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction

“…Recently, our group has shown that morphine (and selective μ-opioid receptor [MOR] agonists, such as DAMGO) specifically impairs CXCL12/CXCR4 signaling in neurons, both in vitro and in vivo, by increasing protein levels of ferritin heavy chain (FHC), a recently described CXCR4 regulator (25,(27)(28)(29). Morphine increases the level of FHC and its association with CXCR4, thereby inhibiting CXCR4 activation and downstream prosurvival signaling pathways (27).…”