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Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause toll-like receptor 4 activation and enhanced pain.

Abstract
We have previously observed that the non-opioid morphine metabolite, morphine-3-glucuronide, enhances pain via a toll-like receptor 4 (TLR4) dependent mechanism. The present studies were undertaken to determine whether TLR4-dependent pain enhancement generalizes to other classes of glucuronide metabolites. In silico modeling predicted that glucuronic acid alone and ethyl glucuronide, a minor but long-lasting ethanol metabolite, would dock to the same MD-2 portion of the TLR4 receptor complex previously characterized as the docking site for morphine-3-glucuronide. Glucuronic acid, ethyl glucuronide and ethanol all caused an increase in TLR4-dependent reporter protein expression in a cell line transfected with TLR4 and associated co-signaling molecules. Glucuronic acid-, ethyl glucuronide-, and ethanol-induced increases in TLR4 signaling were blocked by the TLR4 antagonists LPS-RS and (+)-naloxone. Glucuronic acid and ethyl glucuronide both caused allodynia following intrathecal injection in rats, which was blocked by intrathecal co-administration of the TLR4 antagonist LPS-RS. The finding that ethyl glucuronide can cause TLR4-dependent pain could have implications for human conditions such as hangover headache and alcohol withdrawal hyperalgesia, as well as suggesting that other classes of glucuronide metabolites could have similar effects.
AuthorsSusannah S Lewis, Mark R Hutchinson, Yingning Zhang, Dana K Hund, Steven F Maier, Kenner C Rice, Linda R Watkins
JournalBrain, behavior, and immunity (Brain Behav Immun) Vol. 30 Pg. 24-32 (May 2013) ISSN: 1090-2139 [Electronic] Netherlands
PMID23348028 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
CopyrightCopyright © 2013 Elsevier Inc. All rights reserved.
Chemical References
  • Glucuronides
  • Toll-Like Receptor 4
  • Ethanol
  • Glucuronic Acid
Topics
  • Animals
  • Ethanol (metabolism, pharmacology)
  • Glucuronic Acid (pharmacology)
  • Glucuronides (pharmacology)
  • HEK293 Cells
  • Humans
  • Hyperalgesia (chemically induced, metabolism)
  • Male
  • Pain (chemically induced, metabolism)
  • Pain Measurement
  • Physical Stimulation
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction (drug effects)
  • Toll-Like Receptor 4 (metabolism)

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