Evidence that opioids may have toll-like receptor 4 and MD-2 effects

Hutchinson, Mark R., Zhang, Yingning, Shridhar, Mitesh, Evans, John H., Buchanan, Madison M., Zhao, Tina X., Slivka, Peter F., Coats, Benjamen D., Rezvani, Niloofar, Wieseler, Julie, Hughes, Travis S., Landgraf, Kyle E., Chan, Stefanie, Fong, Stephanie, Phipps, Simon, Falke, Joseph J., Leinwand, Leslie A., Maier, Steven F., Yin, Hang, Rice, Kenner C. and Watkins, Linda R. (2010) Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain, Behavior, and Immunity, 24 1: 83-95. doi:10.1016/j.bbi.2009.08.004

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Author Hutchinson, Mark R.
Zhang, Yingning
Shridhar, Mitesh
Evans, John H.
Buchanan, Madison M.
Zhao, Tina X.
Slivka, Peter F.
Coats, Benjamen D.
Rezvani, Niloofar
Wieseler, Julie
Hughes, Travis S.
Landgraf, Kyle E.
Chan, Stefanie
Fong, Stephanie
Phipps, Simon
Falke, Joseph J.
Leinwand, Leslie A.
Maier, Steven F.
Yin, Hang
Rice, Kenner C.
Watkins, Linda R.
Title Evidence that opioids may have toll-like receptor 4 and MD-2 effects
Journal name Brain, Behavior, and Immunity   Check publisher's open access policy
ISSN 0889-1591
Publication date 2010-01
Year available 2009
Sub-type Article (original research)
DOI 10.1016/j.bbi.2009.08.004
Volume 24
Issue 1
Start page 83
End page 95
Total pages 13
Place of publication Maryland Heights, MO, U.S.A.
Publisher Academic Press
Collection year 2011
Language eng
Formatted abstract
Opioid-induced proinflammatory glial activation modulates wide-ranging aspects of opioid pharmacology
including: opposition of acute and chronic opioid analgesia, opioid analgesic tolerance, opioidinduced
hyperalgesia, development of opioid dependence, opioid reward, and opioid respiratory
depression. However, the mechanism(s) contributing to opioid-induced proinflammatory actions
remains unresolved. The potential involvement of toll-like receptor 4 (TLR4) was examined using
in vitro, in vivo, and in silico techniques. Morphine non-stereoselectively induced TLR4 signaling
in vitro, blocked by a classical TLR4 antagonist and non-stereoselectively by naloxone. Pharmacological
blockade of TLR4 signaling in vivo potentiated acute intrathecal morphine analgesia, attenuated development
of analgesic tolerance, hyperalgesia, and opioid withdrawal behaviors. TLR4 opposition to opioid
actions was supported by morphine treatment of TLR4 knockout mice, which revealed a significant threefold
leftward shift in the analgesia dose response function, versus wildtype mice. A range of structurally
diverse clinically-employed opioid analgesics was found to be capable of activating TLR4 signaling
in vitro. Selectivity in the response was identified since morphine-3-glucuronide, a morphine metabolite
with no opioid receptor activity, displayed significant TLR4 activity, whilst the opioid receptor active
metabolite, morphine-6-glucuronide, was devoid of such properties. In silico docking simulations
revealed ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. An in silico
to in vitro prediction model was built and tested with substantial accuracy. These data provide evidence
that select opioids may non-stereoselectively influence TLR4 signaling and have behavioral consequences
resulting, in part, via TLR4 signaling.
© 2009 Elsevier Inc. All rights reserved.
Keyword Toll-like receptor 4
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online 11 August 2009.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Biomedical Sciences Publications
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Created: Wed, 09 Mar 2011, 14:29:26 EST