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PNAS 109 (16): 6325-6330

Copyright © 2012 by the National Academy of Sciences.


Morphine activates neuroinflammation in a manner parallel to endotoxin

Xiaohui Wanga, Lisa C. Loramb,c, Khara Ramosb,c, Armando J. de Jesusa, Jacob Thomasd, Kui Chenga, Anireddy Reddyb,c, Andrew A. Somogyid, Mark R. Hutchinsone, Linda R. Watkinsb,c, and Hang Yina,c,f,1

aDepartment of Chemistry and Biochemistry, bDepartment of Psychology and Neuroscience, cCenter for Neuroscience, and fBiofrontiers Institute, University of Colorado at Boulder, Boulder, CO 80309; and dDiscipline of Pharmacology and eDiscipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, South Australia, 5005, Australia

Edited* by William F. DeGrado, University of California School of Pharmacy, San Francisco, CA, and approved March 8, 2012 (received for review January 4, 2012)

Abstract: Opioids create a neuroinflammatory response within the CNS, compromising opioid-induced analgesia and contributing to various unwanted actions. How this occurs is unknown but has been assumed to be via classic opioid receptors. Herein, we provide direct evidence that morphine creates neuroinflammation via the activation of an innate immune receptor and not via classic opioid receptors. We demonstrate that morphine binds to an accessory protein of Toll-like receptor 4 (TLR4), myeloid differentiation protein 2 (MD-2), thereby inducing TLR4 oligomerization and triggering proinflammation. Small-molecule inhibitors, RNA interference, and genetic knockout validate the TLR4/MD-2 complex as a feasible target for beneficially modifying morphine actions. Disrupting TLR4/MD-2 protein–protein association potentiated morphine analgesia in vivo and abolished morphine-induced proinflammation in vitro, the latter demonstrating that morphine-induced proinflammation only depends on TLR4, despite the presence of opioid receptors. These results provide an exciting, nonconventional avenue to improving the clinical efficacy of opioids.

Key Words: protein–protein interaction • pain management therapy • drug discovery

Author contributions: X.W., L.C.L., K.R., A.A.S., M.R.H., L.R.W., and H.Y. designed research; X.W., L.C.L., K.R., A.J.d.J., J.T., K.C., and A.R. performed research; X.W., L.C.L., K.R., A.J.d.J., J.T., K.C., A.A.S., M.R.H., L.R.W., and H.Y. analyzed data; and X.W., L.C.L., K.R., M.R.H., L.R.W., and H.Y. wrote the paper.

The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: Hubert.Yin{at}

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