Evidence that opioids may have toll-like receptor 4 and MD-2 effects.
Opioid-induced proinflammatory glial activation modulates wide-ranging aspects of opioid pharmacology including: opposition of acute and chronic opioid analgesia, opioid analgesic tolerance, opioid-induced 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.
Hutchinson
Mark R
MR
Department of Psychology and The Center for Neuroscience, University of Colorado at Boulder, Boulder, CO 80309-0345, USA
Zhang
Yingning
Y
Shridhar
Mitesh
M
Evans
John H
JH
Buchanan
Madison M
MM
Zhao
Tina X
TX
Slivka
Peter F
PF
Coats
Benjamen D
BD
Rezvani
Niloofar
N
Wieseler
Julie
J
Hughes
Travis S
TS
Landgraf
Kyle E
KE
Chan
Stefanie
S
Fong
Stephanie
S
Phipps
Simon
S
Falke
Joseph J
JJ
Leinwand
Leslie A
LA
Maier
Steven F
SF
Yin
Hang
H
Rice
Kenner C
KC
Watkins
Linda R
LR
D000698:Analgesia; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D003198:Computer Simulation; D006358:Hot Temperature; D006930:Hyperalgesia / Q000523:psychology; D007260:Infusion Pumps; D007278:Injections, Spinal; D051218:Lymphocyte Antigen 96 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D014162:Transfection
D000701:Analgesics, Opioid; D051218:Lymphocyte Antigen 96; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D009270:Naloxone
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