Abstract
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.
Highlights
Morphine is the most widely used analgesic worldwide for the management of pain
Mesenteric lymph node (MLN) (n = 9) and liver (n = 10) suspensions were collected after 24 hours, cultured on blood agar plates (BD Biosciences) overnight and the colony forming units (CFUs) were quantified
We show that morphine mediated signaling by m-opioid receptors 1) induced bacterial dissemination into mesenteric lymph node (MLN) and liver of WT mice; 2) compromised intestinal barrier function; and 3) disrupted tight junction organization in gut epithelial cells through a Toll-like receptor (TLR)- dependent mechanism
Summary
Morphine is the most widely used analgesic worldwide for the management of pain. Morphine use is especially prevalent in patients undergoing invasive procedures that are associated with long operative times and extended hospitalization [1,2]. In addition to bacterial translocation, morphine has been documented to increase serum IL-6 levels in rats and accelerate the progression of LPS-induced sepsis to septic shock [6,13,14]. Overall, both clinical and laboratory studies provide evidence that m-opioid receptors are involved in the development and progression of various infectious diseases related to gut pathogens. The objective of the present study was to understand the correlation between morphine treatment and compromised gut barrier function, in order to support the development of novel strategies to treat or prevent gut bacterial infection in opioid-using or -abusing populations
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