title: Morphine activates neuroinflammation in a manner parallel to endotoxin.
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.
authors.affiliation: Department of Chemistry and Biochemistry, Center for Neuroscience, and Biofrontiers Institute, University of Colorado at Boulder, Boulder, CO 80309, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Loram
authors.forename: Khara
authors.initials: K
authors.lastname: Ramos
authors.forename: Armando J
authors.initials: AJ
authors.lastname: de Jesus
authors.forename: Jacob
authors.initials: J
authors.lastname: Thomas
authors.forename: Kui
authors.initials: K
authors.lastname: Cheng
authors.forename: Anireddy
authors.initials: A
authors.lastname: Reddy
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Somogyi
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hutchinson
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
authors.forename: Hang
authors.initials: H
authors.lastname: Yin
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D019281:Dimerization; D004731:Endotoxins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008958:Models, Molecular; D009020:Morphine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015213:Neuroimmunomodulation / Q000187:drug effects; D011485:Protein Binding; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018411:Spodoptera; D051197:Toll-Like Receptor 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D004731:Endotoxins; D053583:Interleukin-1beta; D051218:Lymphocyte Antigen 96; D051197:Toll-Like Receptor 4; D009020:Morphine