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Methods: Male Swiss Webster mice (6-8 weeks) were implanted for 7-days with a morphine (75-mg) or placebo pellet and orally administered sodium butyrate (275 mg/kg) bid Tolerance to antinociception was tested on day-7 using the warm-water tail-withdrawal assay. Resected ileum tissue was incubated in DMEM/F12 for 15-18-hours to allow for the dissolution of AMPs into the media.% Antibacterial activity of the conditioned media was determined by counting the colonies of E. coli (Gram-negative) or L. reuteri (Gram-positive) on agar plates. AMPs, Regenerating islet-derived protein 3-gamma (Reg3g), active against Gram-positive bacteria, and alpha-defensin-5 (Defa5), active against Gram-positive and Gram-negative bacteria, were measured in the ileum using qRT-PCR. Experiments were also conducted in mice treated for 6 days with 0.3 mg/kg fentanyl±butyrate (275 mg/kg) ipbid

Results:% Antibacterial activity against E. coli or L. reuteri of ileum tissue supernatants from chronic morphine-treated mice was significantly reduced compared to that from placebo controls. Chronic morphine or fentanyl administration also significantly down-regulated Reg3g and Defa5 in the ileum. Butyrate prevented opioid-induced decrease in% antibacterial activity and downregulation of AMPs in the ileum. Butyrate-treated mice also did not exhibit tolerance in the warm-water tail-withdrawal assay.

Conclusion: Chronic opioid treatment reduced AMPs in the ileum, implicating a potential mechanism underlying OID. Preventing the opioid-induced decrease in antibacterial activity with sodium butyrate precluded the development of tolerance to antinociception, thus …