The opioid antagonist, β-funaltrexamine, inhibits lipopolysaccharide-induced neuroinflammation and reduces sickness behavior in mice

Brain pathologies such as neurodegenerative diseases, infection, traumatic brain injury, and mood disorders produce enormous personal and economic burdens. It is well established that neuroinflammation plays an important role in the etiology and/or manifestation of such disorders. Previously, we discovered that beta-funaltrexamine (β-FNA) inhibits inflammatory signaling in human astrocytes in vitro, resulting in reduced expression of proinflammatory cytokines/chemokines. The present study examines the effects of peripherally administered β-FNA on lipopolysaccharide (LPS)-induced neuroinflammation and sickness behavior in vivo. Adult male C57BL/6J mice were administered β-FNA and were then immediately administered bacterial lipopolysaccharide (LPS). At 24 h post-injections, sickness behavior was assessed in an open-field test. Following behavioral analysis plasma and brains were collected. Levels of interleukin-6 (IL-6), interferon-γ inducible protein-10 (CXCL10), and monocyte chemoattractant protein-1 (CCL2) were determined by enzyme-linked immunosorbant assay (ELISA). At 24 h post-LPS injection, IL-6, CCL2 and CXCL10 were increased in the plasma, whereas, only CCL2 and CXCL10 were elevated in the brain. β-FNA significantly inhibited LPS-induced CXCL10 and CCL2 expression in brain, but minimally or not at all in the plasma. LPS-induced sickness behavior, as indicated by a reduction in distance moved, was prevented by β-FNA. Overall, CXCL10 expression in the brain was most positively and significantly correlated with sickness behavior; whereas, anxiety-like behavior was most positively and significantly correlated with IL-6 and CCL2 levels in the plasma and levels of CXCL10 and CCL2 in the brain. The reduction in sickness behavior may be in part due to decreased chemokine expression in the brain; further examination of the anti-inflammatory and neuroprotective effects of β-FNA is warranted.