Functions of the Chemokine Receptor CXCR4 in the Central Nervous System and Its Regulation by μ-Opioid Receptors

Abstract

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.

The triplet puzzle theory indicates extensive formation of heteromers between opioid and chemokine receptor subtypes

“…The current results using the triplet puzzle theory Fuxe 2010, 2013) underline that the extensive heteromerization between opioid and chemokine receptor subtypes may exist in the neural-glial networks in the CNS including the participation of immune cells which is supported by previous observations (Suzuki et al 2002;Chen et al 2004;Pello et al 2008;Nash and Meucci 2014;Parsadaniantz et al 2015). Both opioid and chemokine receptor subtypes can be co-located in the same neuronal and non-neuronal cells like astroglia and immune cells (Pello et al 2008;Hutchinson et al 2011;Heinisch et al 2011).…”

“…Recent studies suggest that opioid-chemokine receptor heteromer formation may contribute to HIV-associated neurocognitive disorders (Nash and Meucci 2014).…”

Design and synthesis of a bivalent probe targeting the putative mu opioid receptor and chemokine receptor CXCR4 heterodimer

“…22 This hypothesis has been supported by both studies that substantiated the ability of MOR and CXCR4 to form homodimers [23][24][25][26][27][28][29][30][31] and heterodimers with other GPCRs, [31][32][33][34][35][36] and the finding that the MOR and CXCR4 were co-expressed on immune cells. [37][38][39][40] As demonstrated by previous studies, the use of bivalent ligands can be a powerful strategy to characterize GPCR dimerization/oligomerization. [41][42][43] Therefore, bivalent chemical probes that are capable of interacting with both receptors simultaneously would be invaluable in facilitating the study of the putative MOR-CXCR4 heterodimer and its role in opioid accelerated HIV replication.…”

C-X-C Motif Chemokine 10 Contributes to the Development of Neuropathic Pain by Increasing the Permeability of the Blood–Spinal Cord Barrier

“…This matter may be illuminated through research into chemokines, a family of small cytokines (i.e., signaling proteins) that are upregulated by primary proinflammatory mediators and tumor necrosis factors (15,16). In the CNS, chemokines regulate myriad functions including neuronal development, synaptic transmission, and neuroinflammation (17)(18)(19)(20). Recent studies have shown that the C-X-C motif chemokine receptor 3 (CXCR3) and its ligand C-X-C motif chemokine 10 (CXCL10) are involved in the pathophysiology of allergic itches and neuropathic pain (21)(22)(23).…”