β-Funaltrexamine protects against lipopolysaccharide-induced neuroinflammation and behavioral impairment

Abstract

Background: One of the commonalities present in a multitude of neurological disorders is inflammation. For this reason, targeting inflammation has emerged as a viable option for the potential treatment of neurological disorders. Previous work indicated that beta-funaltrexamine (β-FNA), a selective mu-opioid receptor (MOR) antagonist, not only inhibited inflammatory signaling in vitro in human astroglial cells but also inhibited lipopolysaccharide (LPS)-induced neuroinflammation and sickness-like behavior in mice when administered post-LPS immediately.

Methods: The present study explores the extent to which β-FNA is protective when treatment occurs 10 hours after LPS administration. Male and female C57BL/6J mice were administered LPS (0.83 mg/kg, i.p.) followed by treatment with β-FNA (50 mg/kg, i.p.) immediately or 10h post-LPS. Sickness-like and anxiety-like behavior was assessed using a 10-min open-field test and a 5-min elevated plus-maze test followed by the collection of the whole brain, hippocampus, frontal cortex, cerebellum/brain stem, and plasma. Levels of inflammatory chemokines/cytokines(interferon γ-induced protein, CXCL10; monocyte chemotactic protein 1, CCL2; interleukin-6, IL-6; interleukin-1β, IL-1β, and Tumor Necrosis Factor Alpha, TNF-α) in tissues were measured using an enzyme-linked immunosorbent assay.

Results: Two-way analysis of variance revealed that at 24 hours, LPS increased chemokines and cytokines, and β-FNA treatment was protective depending on the dosing schedule and had region-specific effects. β-FNA inhibited levels of CXCL10 in the hippocampus, frontal cortex, cerebellum/brain stem, and plasma, and more so in males. CCL2 had differential effects between males and females in the frontal cortex, cerebellum/brain stem, and plasma. β-FNA treatment also varied in IL-6, IL-1β, and TNF-α in a region-specific and sex-specific manner. Sickness-like behavior and anxiety-like behavior also differentiated between males and females.

Conclusions: This study indicates that LPS-induced neuroinflammation was differentially affected by βFNA treatment across different brain regions. This shows that the treatment might have a regional effect more than a global one. Sex differences between males and females showed differential effects in the timing of treatment, tissue, and in some cases, even in their response to the LPS-induced stimulation. Further examination of β-FNA’s anti-inflammatory and neuroprotective actions is still necessary.