title: Evidence that opioids may have toll-like receptor 4 and MD-2 effects.
abstract: 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.
authors.affiliation: Department of Psychology and The Center for Neuroscience, University of Colorado at Boulder, Boulder, CO 80309-0345, USA
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hutchinson
authors.forename: Yingning
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mitesh
authors.initials: M
authors.lastname: Shridhar
authors.forename: John H
authors.initials: JH
authors.lastname: Evans
authors.forename: Madison M
authors.initials: MM
authors.lastname: Buchanan
authors.forename: Tina X
authors.initials: TX
authors.lastname: Zhao
authors.forename: Peter F
authors.initials: PF
authors.lastname: Slivka
authors.forename: Benjamen D
authors.initials: BD
authors.lastname: Coats
authors.forename: Niloofar
authors.initials: N
authors.lastname: Rezvani
authors.forename: Julie
authors.initials: J
authors.lastname: Wieseler
authors.forename: Travis S
authors.initials: TS
authors.lastname: Hughes
authors.forename: Kyle E
authors.initials: KE
authors.lastname: Landgraf
authors.forename: Stefanie
authors.initials: S
authors.lastname: Chan
authors.forename: Stephanie
authors.initials: S
authors.lastname: Fong
authors.forename: Simon
authors.initials: S
authors.lastname: Phipps
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Falke
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Leinwand
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
authors.forename: Hang
authors.initials: H
authors.lastname: Yin
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
mesh_terms: 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
chemical_list: 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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