Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity

Hutchinson, M. R., Loram, L. C., Zhang, Y., Shridhar, M., Rezvani, N., Berkelhammer, D., Phipps, S., Foster, P. S., Landgraf, K., Falke, J. J., Rice, K. C., Maier, S. F., Yin, H. and Watkins, L. R. (2010) Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity. Neuroscience, 168 2: 551-563. doi:10.1016/j.neuroscience.2010.03.067

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Author Hutchinson, M. R.
Loram, L. C.
Zhang, Y.
Shridhar, M.
Rezvani, N.
Berkelhammer, D.
Phipps, S.
Foster, P. S.
Landgraf, K.
Falke, J. J.
Rice, K. C.
Maier, S. F.
Yin, H.
Watkins, L. R.
Title Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity
Journal name Neuroscience   Check publisher's open access policy
ISSN 0306-4522
Publication date 2010-06
Year available 2010
Sub-type Article (original research)
DOI 10.1016/j.neuroscience.2010.03.067
Volume 168
Issue 2
Start page 551
End page 563
Total pages 13
Place of publication United Kingdom
Publisher Pergamon
Collection year 2011
Language eng
Subject C1
920111 Nervous System and Disorders
060110 Receptors and Membrane Biology
1109 Neurosciences
Abstract Opioids have been discovered to have Toll-like receptor (TLR) activity, beyond actions at classical opioid receptors. This raises the question whether other pharmacotherapies for pain control may also possess TLR activity, contributing to or opposing their clinical effects. We document that tricyclics can alter TLR4 and TLR2 signaling. In silico simulations revealed that several tricyclics docked to the same binding pocket on the TLR accessory protein, myeloid differentiation protein 2 (MD-2), as do opioids. Eight tricyclics were tested for effects on TLR4 signaling in HEK293 cells over-expressing human TLR4. Six exhibited mild (desipramine), moderate (mianserin, cyclobenzaprine, imiprimine, ketotifen) or strong (amitriptyline) TLR4 inhibition, and no TLR4 activation. In contrast, carbamazepine and oxcarbazepine exhibited mild and strong TLR4 activation, respectively, and no TLR4 inhibition. Amitriptyline but not carbamazepine also significantly inhibited TLR2 signaling in a comparable cell line. Live imaging of TLR4 activation in RAW264.7 cells and TLR4-dependent interleukin-1 release from BV-2 microglia revealed that amitriptyline blocked TLR4 signaling. Lastly, tricyclics with no (carbamazepine), moderate (cyclobenzeprine), and strong (amitriptyline) TLR4 inhibition were tested intrathecally (rats) and amitriptyline tested systemically in wildtype and knockout mice (TLR4 or MyD88). While tricyclics had no effect on basal pain responsivity, they potentiated morphine analgesia in rank-order with their potency as TLR4 inhibitors. This occurred in a TLR4/MyD88-dependent manner as no potentiation of morphine analgesia by amitriptyline occurred in these knockout mice. This suggests that TLR2 and TLR4 inhibition, possibly by interactions with MD2, contributes to effects of tricyclics in vivo. These studies provide converging lines of evidence that several tricyclics or their active metabolites may exert their biological actions, in part, via modulation of TLR4 and TLR2 signaling and suggest that inhibition of TLR4 and TLR2 signaling may potentially contribute to the efficacy of tricyclics in treating chronic pain and enhancing the analgesic efficacy of opioids. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
Keyword (+)-Naloxone
In Silica Docking
tricyclic anti-depressants
Innate immunology
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Biomedical Sciences Publications
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Citation counts: TR Web of Science Citation Count  Cited 44 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 48 times in Scopus Article | Citations
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Created: Sun, 20 Jun 2010, 00:02:24 EST