Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause toll-like receptor 4 activation and enhanced pain.
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.
Department of Psychology & Neuroscience, University of Colorado at Boulder, Boulder, CO 80309-0345, USA.
Susannah S
SS
Lewis
Mark R
MR
Hutchinson
Yingning
Y
Zhang
Dana K
DK
Hund
Steven F
SF
Maier
Kenner C
KC
Rice
Linda R
LR
Watkins
D000818:Animals; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D020723:Glucuronic Acid / Q000494:pharmacology*; D020719:Glucuronides / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D010146:Pain / Q000139:chemically induced* / Q000378:metabolism; D010147:Pain Measurement; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D020719:Glucuronides; D051197:Toll-Like Receptor 4; D000431:Ethanol; D020723:Glucuronic Acid