Morphine induces bacterial translocation in mice by compromising intestinal barrier function in a TLR-dependent manner.
Opiates are among the most prescribed drugs for pain management. However, morphine use or abuse results in significant gut bacterial translocation and predisposes patients to serious infections with gut origin. The mechanism underlying this defect is still unknown. In this report, we investigated the mechanisms underlying compromised gut immune function and bacterial translocation following morphine treatment. We demonstrate significant bacterial translocation to mesenteric lymph node (MLN) and liver following morphine treatment in wild-type (WT) animals that was dramatically and significantly attenuated in Toll-like receptor (TLR2 and 4) knockout mice. We further observed significant disruption of tight junction protein organization only in the ileum but not in the colon of morphine treated WT animals. Inhibition of myosin light chain kinase (MLCK) blocked the effects of both morphine and TLR ligands, suggesting the role of MLCK in tight junction modulation by TLR. This study conclusively demonstrates that morphine induced gut epithelial barrier dysfunction and subsequent bacteria translocation are mediated by TLR signaling and thus TLRs can be exploited as potential therapeutic targets for alleviating infections and even sepsis in morphine-using or abusing populations.
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
Jingjing
J
Meng
Haidong
H
Yu
Jing
J
Ma
Jinghua
J
Wang
Santanu
S
Banerjee
Rick
R
Charboneau
Roderick A
RA
Barke
Sabita
S
Roy
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D018988:Bacterial Translocation / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D007082:Ileum / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000382:microbiology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D008643:Mesentery; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009020:Morphine / Q000494:pharmacology*; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
D000701:Analgesics, Opioid; D001381:Azepines; D009281:Naphthalenes; D017450:Receptors, Opioid, mu; C569043:Tjp1 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D062826:Zonula Occludens-1 Protein; C070571:ML 7; D009020:Morphine; D009219:Myosin-Light-Chain Kinase