Functions of the chemokine receptor CXCR4 in the central nervous system and its regulation by μ-opioid receptors.

Activation of the G protein-coupled receptor CXCR4 by its chemokine ligand CXCL12 regulates a number of physiopathological functions in the central nervous system, during development as well as later in life. In addition to the more classical roles of the CXCL12/CXCR4 axis in the recruitment of immune cells or migration and proliferation of neural precursor cells, recent studies suggest that CXCR4 signaling also modulates synaptic function and neuronal survival in the mature brain, through direct and indirect effects on neurons and glia. These effects, which include regulation of glutamate receptors and uptake, and of dendritic spine density, can significantly alter the ability of neurons to face excitotoxic insults. Therefore, they are particularly relevant to neurodegenerative diseases featuring alterations of glutamate neurotransmission, such as HIV-associated neurocognitive disorders. Importantly, CXCR4 signaling can be dysregulated by HIV viral proteins, host HIV-induced factors, and opioids. Potential mechanisms of opioid regulation of CXCR4 include heterologous desensitization, transcriptional regulation and changes in receptor expression levels, opioid-chemokine receptor dimer or heteromer formation, and the newly described modulation by the protein ferritin heavy chain-all leading to inhibition of CXCR4 signaling. After reviewing major effects of chemokines and opioids in the CNS, this chapter discusses chemokine-opioid interactions in neuronal and immune cells, focusing on their potential contribution to HIV-associated neurocognitive disorders.