Glucuronic Acid and the Ethanol Metabolite Ethyl-glucuronide Cause Toll-like Receptor 4 Activation and Enhanced Pain

Overview

Journal Brain Behav Immun

Publisher Elsevier

Specialties Allergy & Immunology
Neurology
Psychiatry

Date 2013 Jan 26

PMID 23348028

Citations 36

Authors

Susannah S Lewis

Mark R Hutchinson

Yingning Zhang

Dana K Hund

Steven F Maier

Kenner C Rice

Linda R Watkins

Affiliations

Soon will be listed here.

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.

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