Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/135282
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Type: Journal article
Title: Toll-Like Receptors change morphine-induced antinociception, tolerance and dependence: studies using male and female TLR and Signalling gene KO mice
Author: Thomas, J.H.L.
Lui, L.
Abell, A.
Tieu, W.
Somogyi, A.A.
Bajic, J.E.
Hutchinson, M.R.
Citation: Brain, Behavior, and Immunity, 2022; 102:71-85
Publisher: Elsevier
Issue Date: 2022
ISSN: 0889-1591
1090-2139
Statement of
Responsibility: 
Jacob H.L. Thomas, Liang Lui, Andrew Abell, William Tieu, Andrew A. Somogyi, Juliana E. Bajic, Mark R. Hutchinson
Abstract: Toll-like receptors (TLR) have been proposed as a site of action that alters opioid pharmacodynamics. However, a comprehensive assessment of acute opioid antinociception, tolerance and withdrawal behaviours in genetic null mutant strains with altered innate immune signalling has not been performed. Nor has the impact of genetic deletion of TLR2/4 on high-affinity opioid receptor binding. Here we show that diminished TLR signalling po- tentiates acute morphine antinociception equally in male and female mice. However, only male TIR8 null mutant mice showed reduced morphine analgesia. Analgesic tolerance was prevented in TLR2 and TLR4 null mutants, but not MyD88 animals. Withdrawal behaviours were only protected in TLR2 -/- mice. In silico docking simu- lations revealed opioid ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. There was no binding of [3H](-)-naloxone or [3H]diprenorphine to TLR4 in the concentrations explored. These data confirm that opioids have high efficacy activity at innate immune pattern recognition binding sites but do not bind to TLR4 and identify critical pathway and sex-specific effects of the complex innate immune signalling contributions to opioid pharmacodynamics. These data further support the behavioural importance of the TLR- opioid interaction but fail to demonstrate direct evidence for high-affinity binding of the TLR4 signalling complex to ligands.
Keywords: Toll-like receptors
morphine
analgesia
tolerance
withdrawal
opioid receptor
binding kinetics
Rights: © 2022 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.bbi.2022.02.001
Grant ID: http://purl.org/au-research/grants/arc/FT180100565
Published version: http://dx.doi.org/10.1016/j.bbi.2022.02.001
Appears in Collections:Medical Sciences publications

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