Research and Development

@article{Wang2012,

title = {Morphine activates neuroinflammation in a manner parallel to endotoxin},

author = {Xiaohui Wang and Lisa C. Loram and Khara Ramos and Armando J. de Jesus and Jacob Thomas and Kui Cheng and Anireddy Reddy and Andrew A. Somogyi and Mark R. Hutchinson and Linda R. Watkins and Hang Yin},

url = {https://www.pnas.org/content/109/16/6325.long},

doi = {10.1073/pnas.1200130109},

year  = {2012},

date = {2012-04-17},

journal = {Proceedings of the National Academy of Sciences of the United States of America},

volume = {109},

number = {16},

pages = {6325-6330},

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.},

keywords = {drug discovery, pain management therapy, protein–protein interaction},

pubstate = {published},

tppubtype = {article}

}