The opioid antagonist, β-funaltrexamine, inhibits NF-κB signaling and chemokine expression in human astrocytes and in mice

Abstract

Opioid-immune crosstalk occurs when opioid drugs alter the activity of the immune system. In this study, the opioid antagonist β-funaltrexamine (β-FNA) decreases the expression and release of an inflammatory chemokine, interferon-γ inducible protein-10 (CXCL10) from normal human astrocytes stimulated by interleukin 1β (IL-1β). β-FNA decreased CXCL10 by an unknown action that did not involve the mu opioid receptor (MOR). As IL-1β acts through its receptor to activate NF-κB/MAPK signaling pathways which leads to CXCL10 expression and release, key steps in the IL-1β signaling pathways were examined following β-FNA treatment. IL-1β-induced activation of p38 mitogen-activated protein kinases (p38 MAPK) was inhibited by β-FNA as shown by decreased p38 MAPK phosphorylation in treated cells. β-FNA also decreased the levels of activated subunits of NF-κB (p50 and p65) in treated astrocytes. The impact of β-FNA was also observed in proteins that act to negatively regulate NF-κB signaling. IL-1β upregulated the expression of A20, a ubiquitin (Ub)-editing enzyme that dampens NF-κB signaling by altering ubiquination patterns on IL-1 receptor second messengers, and the increase in A20 was significantly inhibited by β-FNA treatment. Inhibition of the Ub-activating enzyme E1 by the inhibitor PYR41 also decreased CXCL10 release, like β-FNA, and concurrent treatment with both PYR41 and β-FNA inhibited CXCL10 more than did either agent alone. In mice, lipopolysaccharide-induced CXCL10 expression in the brain was inhibited by treatment with β-FNA. These findings suggest that β-FNA exerts an anti-inflammatory action in vitro and in vivo that is MOR-independent and possibly due to the alkylating ability of β-FNA.

The TLR4-Active Morphine Metabolite Morphine-3-Glucuronide Does Not Elicit Macrophage Classical Activation In Vitro

“…Our results indicate that the LPS-induced expression of IL6 and chemokines CXCL10 and CXCL11 is affected by M3G and interestingly, the inhibition does not seem to depend on the concentration of M3G. In agreement with our results, opioid receptor-independent inhibition of LPS-induced CXCL10 expression in the brain of mice by treatment with the opioid antagonist β-funaltrexamine has been documented (Davis et al, 2015). …”

Single cell transcriptomics reveals opioid usage evokes widespread suppression of antiviral gene program

“…Reports from Hutchinson et al 18 and Wang et al 19 have shown that morphine activates the TLR4 receptor through a MOR-independent pathway in glial populations in the CNS and contributes to drug reinforcement. Opioid antagonist, β-funaltrexamine also has been shown to inhibit NFkB signaling and chemokine expression in human astrocytes and inhibit LPSinduced neuroinflammation in mice 20,21 . However, these studies usually focus on a few genes and in a particular cell type.…”

“…10X Genomics). b t-SNE plot of naive (51,041) and LPS (100 ng/mL)-treated(21,873) PBMCs were clustered (cells were filtered based on >300 and <2000 genes per cell, <10,000 UMIs per cell; see Methods) and identified into immune populations (top) and visualized by control individuals and opioid-dependent individuals in each state (bottom): naive state control samples 1-7 (C1-C7), naive state opioid-dependent samples 1-7 (O1-O7), LPStreated control samples 1-3 (C1-C3 (LPS)), LPS-treated opioid-dependent samples 1-3 (O1-O3 (LPS)). c Volcano plot showing fold change of gene expression (log2 scale) for downregulated (Control) and upregulated (Opioid) genes for opioid-dependent cells compared to non-dependent controls for naive state populations: monocytes and LPS-treated populations: NK cells, CD4+ T cells, and activated T cells (x-axis) with a significance of 0.05 (y-axis, −log10 scale).…”

Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation

“…Recent studies have demonstrated that the MAPK family, including p38 MAPK, extracellular signal-regulated protein kinase (ERK), and c-Jun N-terminal kinase, plays important roles in morphine tolerance [34–36]. The expression of pro-inflammatory cytokines and other harmful signaling molecules is regulated by p38 MAPK/NF-κB signaling pathway in the CNS [37].…”