Proceedings of the National Academy of Sciences - PNAS, 2012-04, Vol.109 (16), p.6325-6330
2012
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- Autor(en) / Beteiligte
- Titel
- Morphine activates neuroinflammation in a manner parallel to endotoxin
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2012-04, Vol.109 (16), p.6325-6330
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1200130109Titel-ID: cdi_pubmed_primary_22474354
- Format
- –
- Schlagworte
- Analgesia, Analgesics, Analgesics, Opioid - metabolism, Analgesics, Opioid - pharmacology, Animals, Antibodies, Behavioral neuroscience, Biological Sciences, Blotting, Western, Cell Line, Central nervous system, Differentiation, Dimerization, Endotoxins, Endotoxins - chemistry, Endotoxins - metabolism, Endotoxins - pharmacology, Female, HEK293 Cells, Humans, Inflammation, Interleukin-1beta - genetics, Interleukin-1beta - metabolism, Lymphocyte Antigen 96 - chemistry, Lymphocyte Antigen 96 - genetics, Lymphocyte Antigen 96 - metabolism, Male, Messenger RNA, Mice, Mice, Inbred BALB C, Mice, Knockout, Models, Molecular, Morphine, Morphine - chemistry, Morphine - metabolism, Morphine - pharmacology, Narcotics, Neuroimmunomodulation - drug effects, Oligomerization, Opioid analgesics, Opioid receptors, Pain perception, Physical Sciences, Protein Binding, Proteins, Rats, Rats, Sprague-Dawley, Receptors, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, RNA-mediated interference, Spodoptera, T cell receptors, TLR4 protein, Toll like receptors, Toll-Like Receptor 4 - chemistry, Toll-Like Receptor 4 - genetics, Toll-Like Receptor 4 - metabolism, Toxins