title: 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.
authors.affiliation: Department of Pharmacology/Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK 74107, USA. Electronic address: randall.davis@okstate.edu.
authors.forename: Randall L
authors.initials: RL
authors.lastname: Davis
authors.affiliation: Department of Pharmacology/Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK 74107, USA.
authors.forename: Subhas
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Pharmacology/Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK 74107, USA.
authors.forename: J
authors.initials: J
authors.lastname: Thomas Curtis
authors.affiliation: Department of Pharmacology/Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK 74107, USA.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Stevens
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000166:cytology; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D054357:Chemokine CXCL10; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009292:Narcotic Antagonists; D009271:Naltrexone; C024524:beta-funaltrexamine
keywords: Astrocyte; Chemokine; Cytokine; IL-1β; NF-κB; Opioid; β-FNA