Toll-like receptors change morphine-induced antinociception, tolerance and dependence: Studies using male and female TLR and signalling gene KO mice

Authors

Jacob H. Thomas, Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia; Discipline of Physiology, Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia.
Liang Lui, Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia.
Andrew Abell, Discipline of Physiology, Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia; ARC Centre for Nanoscale BioPhotonics, University of Adelaide, SA 5005, Australia.
William Tieu, Discipline of Chemistry, University of Adelaide, Adelaide, SA 5005, Australia.
Andrew A. Somogyi, Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia.
Juliana E. Bajic, Discipline of Physiology, Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia; ARC Centre for Nanoscale BioPhotonics, University of Adelaide, SA 5005, Australia.
Mark R. Hutchinson, Advocate Aurora Health

Recommended Citation

Thomas JHL, Lui L, Abell A, et al. Toll-like receptors change morphine-induced antinociception, tolerance and dependence: Studies using male and female TLR and signalling gene KO mice. Brain Behav Immun. 2022;102:71-85. doi:10.1016/j.bbi.2022.02.001

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 potentiates 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 simulations 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.

Type

Article

PubMed ID

35131445