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

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

doi:10.1016/j.bbi.2009.08.004

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

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

Research output: Contribution to journal › Article › peer-review

464 Scopus citations

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.

Original language	English
Pages (from-to)	83-95
Number of pages	13
Journal	Brain, Behavior, and Immunity
Volume	24
Issue number	1
DOIs	https://doi.org/10.1016/j.bbi.2009.08.004
State	Published - Jan 2010

Funding

This work was supported by an International Association for the Study of Pain International Collaborative grant, American Australian Association Merck Company Foundation Fellowship, National Health and Medical Research Council CJ Martin Fellowship ( ID 465423 ; M.R.H.) and NIH Grants DA015642 , DA017670 , DA024044 , DE017782 , T32 GM-065103 , and DE017782 . This work was partially supported by the by the NIH Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. H.Y. thanks the Council on Research and Creative Work at the University of Colorado at Boulder and the Kimmel Foundation (SKF-08-101) for financial support of the work. M.S., T.X.Z. and M.M.B. are grateful for HHMI undergraduate grants for biomedical research provided by the Undergraduate Research Opportunities Program at the University of Colorado at Boulder. P.F.S. thanks for the University of Colorado Pre-doctoral Training program in Molecular Biophysics (T32 GM-065103). We thank Avigen (Alameda, CA, USA) for the gift of the HEK293-TLR4 cell line and AV411. Thanks to the Akira Research group, Osaka University, Osaka, Japan for permission to use the TLR4 knockout mice.

Funders	Funder number
DA015642, T32 GM-065103, DE017782, DA017670
Howard Hughes Medical Institute
K05DA024044
University of Colorado Boulder
SKF-08-101
465423

Keywords

Analgesia
Dependence
Glia
Knockout
Microglia
Opioid
Toll-like receptor 4

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10.1016/j.bbi.2009.08.004

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Hutchinson, M. R., Zhang, Y., Shridhar, M., Evans, J. H., Buchanan, M. M., Zhao, T. X., Slivka, P. F., Coats, B. D., Rezvani, N., Wieseler, J., Hughes, T. S., Landgraf, K. E., Chan, S., Fong, S., Phipps, S., Falke, J. J., Leinwand, L. A., Maier, S. F., Yin, H., ... Watkins, L. R. (2010). Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain, Behavior, and Immunity, 24(1), 83-95. https://doi.org/10.1016/j.bbi.2009.08.004

@article{ed97139986bd4209813950b01939136d,

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.",

keywords = "Analgesia, Dependence, Glia, Knockout, Microglia, Opioid, Toll-like receptor 4",

author = "Hutchinson, \{Mark R.\} and Yingning Zhang and Mitesh Shridhar and Evans, \{John H.\} and Buchanan, \{Madison M.\} and Zhao, \{Tina X.\} and Slivka, \{Peter F.\} and Coats, \{Benjamen D.\} and Niloofar Rezvani and Julie Wieseler and Hughes, \{Travis S.\} and Landgraf, \{Kyle E.\} and Stefanie Chan and Stephanie Fong and Simon Phipps and Falke, \{Joseph J.\} and Leinwand, \{Leslie A.\} and Maier, \{Steven F.\} and Hang Yin and Rice, \{Kenner C.\} and Watkins, \{Linda R.\}",

note = "Funding Information: This work was supported by an International Association for the Study of Pain International Collaborative grant, American Australian Association Merck Company Foundation Fellowship, National Health and Medical Research Council CJ Martin Fellowship ( ID 465423 ; M.R.H.) and NIH Grants DA015642 , DA017670 , DA024044 , DE017782 , T32 GM-065103 , and DE017782 . This work was partially supported by the by the NIH Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. H.Y. thanks the Council on Research and Creative Work at the University of Colorado at Boulder and the Kimmel Foundation (SKF-08-101) for financial support of the work. M.S., T.X.Z. and M.M.B. are grateful for HHMI undergraduate grants for biomedical research provided by the Undergraduate Research Opportunities Program at the University of Colorado at Boulder. P.F.S. thanks for the University of Colorado Pre-doctoral Training program in Molecular Biophysics (T32 GM-065103). We thank Avigen (Alameda, CA, USA) for the gift of the HEK293-TLR4 cell line and AV411. Thanks to the Akira Research group, Osaka University, Osaka, Japan for permission to use the TLR4 knockout mice. ",

year = "2010",

month = jan,

doi = "10.1016/j.bbi.2009.08.004",

language = "English",

volume = "24",

pages = "83--95",

journal = "Brain, Behavior, and Immunity",

issn = "0889-1591",

publisher = "Academic Press Inc.",

number = "1",

}

Hutchinson, MR, Zhang, Y, Shridhar, M, Evans, JH, Buchanan, MM, Zhao, TX, Slivka, PF, Coats, BD, Rezvani, N, Wieseler, J, Hughes, TS, Landgraf, KE, Chan, S, Fong, S, Phipps, S, Falke, JJ, Leinwand, LA, Maier, SF, Yin, H, Rice, KC & Watkins, LR 2010, 'Evidence that opioids may have toll-like receptor 4 and MD-2 effects', Brain, Behavior, and Immunity, vol. 24, no. 1, pp. 83-95. https://doi.org/10.1016/j.bbi.2009.08.004

TY - JOUR

T1 - Evidence that opioids may have toll-like receptor 4 and MD-2 effects

AU - Hutchinson, Mark R.

AU - Zhang, Yingning

AU - Shridhar, Mitesh

AU - Evans, John H.

AU - Buchanan, Madison M.

AU - Zhao, Tina X.

AU - Slivka, Peter F.

AU - Coats, Benjamen D.

AU - Rezvani, Niloofar

AU - Wieseler, Julie

AU - Hughes, Travis S.

AU - Landgraf, Kyle E.

AU - Chan, Stefanie

AU - Fong, Stephanie

AU - Phipps, Simon

AU - Falke, Joseph J.

AU - Leinwand, Leslie A.

AU - Maier, Steven F.

AU - Yin, Hang

AU - Rice, Kenner C.

AU - Watkins, Linda R.

N1 - Funding Information: This work was supported by an International Association for the Study of Pain International Collaborative grant, American Australian Association Merck Company Foundation Fellowship, National Health and Medical Research Council CJ Martin Fellowship ( ID 465423 ; M.R.H.) and NIH Grants DA015642 , DA017670 , DA024044 , DE017782 , T32 GM-065103 , and DE017782 . This work was partially supported by the by the NIH Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. H.Y. thanks the Council on Research and Creative Work at the University of Colorado at Boulder and the Kimmel Foundation (SKF-08-101) for financial support of the work. M.S., T.X.Z. and M.M.B. are grateful for HHMI undergraduate grants for biomedical research provided by the Undergraduate Research Opportunities Program at the University of Colorado at Boulder. P.F.S. thanks for the University of Colorado Pre-doctoral Training program in Molecular Biophysics (T32 GM-065103). We thank Avigen (Alameda, CA, USA) for the gift of the HEK293-TLR4 cell line and AV411. Thanks to the Akira Research group, Osaka University, Osaka, Japan for permission to use the TLR4 knockout mice.

PY - 2010/1

Y1 - 2010/1

N2 - 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.

AB - 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.

KW - Analgesia

KW - Dependence

KW - Glia

KW - Knockout

KW - Microglia

KW - Opioid

KW - Toll-like receptor 4

UR - https://www.scopus.com/pages/publications/71749111875

U2 - 10.1016/j.bbi.2009.08.004

DO - 10.1016/j.bbi.2009.08.004

M3 - Article

C2 - 19679181

AN - SCOPUS:71749111875

SN - 0889-1591

VL - 24

SP - 83

EP - 95

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

IS - 1

ER -

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

Abstract

Funding

Keywords

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