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|Title:||Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause toll-like receptor 4 activation and enhanced pain|
|Citation:||Brain Behavior and Immunity, 2013; 30:24-32|
|Publisher:||Academic Press Inc|
|Susannah S. Lewis, Mark R.Hutchinson, Yingning Zhang, Dana K.Hund, Steven F.Maier, Kenner C. Rice, Linda R.Watkins|
|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.|
|Keywords:||Glucuronic acid; Ethanol; Ethyl glucuronide; TLR4; (+)-Naloxone; Glucoronidation; Metabolite; Dextro-naloxone|
|Rights:||Copyright © 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.|
|Appears in Collections:||Physiology publications|
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