Document Detail


Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause toll-like receptor 4 activation and enhanced pain.
MedLine Citation:
PMID:  23348028     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Susannah S Lewis; Mark R Hutchinson; Yingning Zhang; Dana K Hund; Steven F Maier; Kenner C Rice; Linda R Watkins
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural     Date:  2013-01-21
Journal Detail:
Title:  Brain, behavior, and immunity     Volume:  30     ISSN:  1090-2139     ISO Abbreviation:  Brain Behav. Immun.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-30     Completed Date:  2013-10-22     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  8800478     Medline TA:  Brain Behav Immun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  24-32     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
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*
Grant Support
ID/Acronym/Agency:
DA023132/DA/NIDA NIH HHS; DA024044/DA/NIDA NIH HHS; DE017782/DE/NIDCR NIH HHS; K05 DA024044/DA/NIDA NIH HHS; R01 DA023132/DA/NIDA NIH HHS; R01 DE017782/DE/NIDCR NIH HHS; R01 DE021966/DE/NIDCR NIH HHS
Chemical
Reg. No./Substance:
0/Glucuronides; 0/Toll-Like Receptor 4; 3K9958V90M/Ethanol; 8A5D83Q4RW/Glucuronic Acid
Comments/Corrections

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