| Evidence that opioids may have toll-like receptor 4 and MD-2 effects. | |
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MedLine Citation:
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PMID: 19679181 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Mark R Hutchinson; Yingning Zhang; Mitesh Shridhar; John H Evans; Madison M Buchanan; Tina X Zhao; Peter F Slivka; Benjamen D Coats; Niloofar Rezvani; Julie Wieseler; Travis S Hughes; Kyle E Landgraf; Stefanie Chan; Stephanie Fong; Simon Phipps; Joseph J Falke; Leslie A Leinwand; Steven F Maier; Hang Yin; Kenner C Rice; Linda R Watkins |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't Date: 2009-08-11 |
Journal Detail:
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Title: Brain, behavior, and immunity Volume: 24 ISSN: 1090-2139 ISO Abbreviation: Brain Behav. Immun. Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2009-11-30 Completed Date: 2010-02-17 Revised Date: 2011-12-02 |
Medline Journal Info:
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Nlm Unique ID: 8800478 Medline TA: Brain Behav Immun Country: United States |
Other Details:
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Languages: eng Pagination: 83-95 Citation Subset: IM |
Affiliation:
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Department of Psychology and The Center for Neuroscience, University of Colorado at Boulder, Boulder, CO 80309-0345, USA |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Analgesia Analgesics, Opioid / pharmacology* Animals Cell Line Computer Simulation Hot Temperature / diagnostic use Hyperalgesia / psychology Infusion Pumps Injections, Spinal Lymphocyte Antigen 96 / agonists, antagonists & inhibitors, drug effects* Macrophages / drug effects Male Mice Naloxone / pharmacology Narcotic Antagonists / pharmacology Pain Measurement Rats Rats, Sprague-Dawley Reaction Time / drug effects Receptors, Opioid, mu / agonists, antagonists & inhibitors, drug effects Signal Transduction / drug effects Substance Withdrawal Syndrome / psychology Toll-Like Receptor 4 / agonists, antagonists & inhibitors, drug effects* Transfection |
| Grant Support | |
ID/Acronym/Agency:
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DA015642/DA/NIDA NIH HHS; DA017670/DA/NIDA NIH HHS; DA024044/DA/NIDA NIH HHS; DE017782/DE/NIDCR NIH HHS; K02 DA015642-05/DA/NIDA NIH HHS; K05 DA024044-02/DA/NIDA NIH HHS; R01 DA017670-05/DA/NIDA NIH HHS; R01 DA023132-02/DA/NIDA NIH HHS; R01 DA023132-05/DA/NIDA NIH HHS; R01 DE017782-02/DE/NIDCR NIH HHS; R01 DE017782-03/DE/NIDCR NIH HHS; R01 DE017782-04/DE/NIDCR NIH HHS; T32 GM-065103/GM/NIGMS NIH HHS; //Howard Hughes Medical Institute |
| Chemical | |
Reg. No./Substance:
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0/Analgesics, Opioid; 0/Lymphocyte Antigen 96; 0/Narcotic Antagonists; 0/Receptors, Opioid, mu; 0/Tlr4 protein, rat; 0/Toll-Like Receptor 4; 465-65-6/Naloxone |
| Comments/Corrections | |
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