ArticleBritish journal of pharmacology2013
Pharmacological characterization of LPS and opioid interactions at the toll-like receptor 4.
Article in British journal of pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 91 citations in OpenAlex.
- Spinal neuronal TLR4-induced enhancement of nociceptive signals contributes to myocardial ischemia/reperfusion injury.Basic research in cardiology · 2026Article
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- Comparative effects of fentanyl, morphine, and hydromorphone on postoperative delirium and outcomes after cardiac surgery: a propensity score-matched cohort study.Scientific reports · 2025Article
- Precision Adjuvant Strategies in Vaccine Development for Substance Use Disorders: Variability and Mechanistic Insights.Pharmaceutics · 2025Review
- The immunological and pharmacokinetic evaluation of Lipid-PLGA hybrid nanoparticle-based oxycodone vaccines.Biomaterials · 2025Article
- Determining theFrontiers in microbiology · 2025Article
- Real-time monitoring with iTLR4 assay identifies ligand-dependent TLR4-TLR4 conformational dynamics.Frontiers in immunology · 2025Article
- The effects of chronic, continuous β-funaltrexamine pre-treatment on lipopolysaccharide-induced inflammation and behavioral deficits in C57BL/6J mice.Journal of inflammation (London, England) · 2024Article
- Fentanyl Overdose Causes Prolonged Cardiopulmonary Dysregulation in Male SKH1 Mice.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Review
- Methadone Requires the Co-Activation of μ-Opioid and Toll-Like-4 Receptors to Produce Extracellular DNA Traps in Bone-Marrow-Derived Mast Cells.International journal of molecular sciences · 2024Article
- Fentanyl dysregulates neuroinflammation and disrupts blood-brain barrier integrity in HIV-1 Tat transgenic mice.Journal of neurovirology · 2024Article
- Fentanyl enhances immune cell response through TLR4/MD-2 complex.Frontiers in pharmacology · 2024Article
- Article
- Inhibition of the NLRP3 Inflammasome Activation/Assembly through the Activation of the PI3K Pathway by Naloxone Protects Neural Stem Cells from Ischemic Condition.Molecular neurobiology · 2023Article
- A lipidated TLR7/8 adjuvant enhances the efficacy of a vaccine against fentanyl in mice.NPJ vaccines · 2023Article
- Evaluation of Antimicrobial Activities against VariousMolecules (Basel, Switzerland) · 2023Article
- Sex-specific inflammatory and white matter effects of prenatal opioid exposure: a pilot study.Pediatric research · 2023Article
- Macrophage-derived exosomal aminopeptidase N aggravates sepsis-induced acute lung injury by regulating necroptosis of lung epithelial cell.Communications biology · 2022Article
- Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 1 institution in 1 country.
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Abstract
background and purposePrevious work in our laboratory showed opioid agents inhibit cytokine expression in astrocytes. Recently, Watkins and colleagues hypothesized that opioid agonists activate toll-like receptor 4 (TLR4) signalling, which leads to neuroinflammation. To test this hypothesis, we characterized LPS and opioid effects on TLR4 signalling in reporter cells. EXPERIMENTAL APPROACH: NF-κB reporter cells expressing high levels of TLR4 were used to compare LPS and opioid effects on NF-κB activation, a pathway activated by TLR4 stimulation. KEY
resultsLPS increased TLR4 signalling in a concentration-dependent manner and was antagonized by LPS antagonist (LPS-RS, from Rhodobacter sphaeroides). A concentration ratio analysis showed that LPS-RS was a competitive antagonist. The opioid agonists, morphine and fentanyl, produced minor activation of TLR4 signalling when given alone. When tested following LPS stimulation, opioid agonists inhibited NF-κB activation but this inhibition was not blocked by the general opioid antagonist, naloxone, nor by the selective μ opioid receptor antagonist, β-FNA. Indeed, both naloxone and β-FNA also inhibited NF-κB activation in reporter cells. Further examination of fentanyl and β-FNA effects revealed that both opioid agents inhibited LPS signalling in a non-competitive fashion. CONCLUSIONS AND IMPLICATIONS: These results show that LPS-RS is a competitive antagonist at the TLR4 complex, and that both opioid agonists and antagonists inhibit LPS signalling in a non-competitive fashion through a non-GPCR, opioid site(s) in the TLR4 signalling pathway. If confirmed, existing opioid agents or other drug molecules more selective at this novel site may provide a new therapeutic approach to the treatment of neuroinflammation.
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