ArticleBritish journal of pharmacology2016
Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4.
Article in British journal of pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 3 registered trials, which are not on this map. Cited by 88 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Clinical Trial to Assess a Single Dose of Low-Dose Naltrexone and Acetaminophen Combination and Its Components in the Acute Treatment of Migraine
Safety and Efficacy of Naltrexone/Acetaminophen for the Acute Treatment of Migraine: A Single-Site, Phase 2 Randomized Trial
A Clinical Trial to Assess a Single Dose of Low-Dose Naltrexone and Acetaminophen Combination and Its Components in the Acute Treatment of Migraine
Who cites it
88 citing papers in PubMed, 1 synthesis or guideline pooled it, 167 citations in OpenAlex.
- Psychopharmacological Therapy Positively Modulates Disease Activity in Inflammatory Bowel Disease: A Systematic Review.International journal of molecular sciences · 2025Pooled it
- Low dose Naltrexone for induction of remission in inflammatory bowel disease patients.Journal of translational medicine · 2018Trial
- Low-Dose Naltrexone: What is the Evidence? A Narrative Review.Advances in therapy · 2026Review
- Morphine disrupts antigen-presenting cell function through TLR-4 and autophagy pathways.Molecular biology reports · 2026Article
- The actions of morphine on microglia and the underlying effects on associated adverse effects.Psychopharmacology · 2026Review
- Low-Dose Naltrexone in Chronic Pain Management: Mechanisms, Evidence, and Clinical Implications.Journal of personalized medicine · 2026Review
- Low dose naltrexone for fibromyalgia: case series demonstrating pain relief and other health benefits.Frontiers in pain research (Lausanne, Switzerland) · 2026Article
- Epidermal growth factor receptor signaling modulates postoperative pain and inflammatory responses.Frontiers in immunology · 2026Review
- Potential roles for microglia in drug addiction: Adolescent neurodevelopment and beyond.Journal of neuroimmunology · 2025Review
- Microglial activation as a hallmark of neuroinflammation in Alzheimer's disease.Metabolic brain disease · 2025Review
- Emerging role of macrophages in neuropathic pain.Journal of orthopaedic translation · 2025Review
- Real-time monitoring with iTLR4 assay identifies ligand-dependent TLR4-TLR4 conformational dynamics.Frontiers in immunology · 2025Article
- Naltrexone blocks alcohol-induced effects on kappa-opioid receptors in the plasma membrane.Translational psychiatry · 2024Article
- Human IPSC-Derived PreBötC-Like Neurons and Development of an Opiate Overdose and Recovery Model.Advanced biology · 2024Article
- Novel medications for problematic alcohol use.The Journal of clinical investigation · 2024Review
- Microglia in drug addiction: A perspective from neuroimmunopharmacology.Zoological research · 2024Article
- Neuroinflammation of Microglial Regulation in Alzheimer's Disease: Therapeutic Approaches.Molecules (Basel, Switzerland) · 2024Review
- Review
- The HMGB1-RAGE axis in nucleus accumbens facilitates cocaine-induced conditioned place preference via modulating microglial activation.Brain and behavior · 2024Article
- Effective Doses of Low-Dose Naltrexone for Chronic Pain - An Observational Study.Journal of pain research · 2024Article
28 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 4 institutions in 3 countries.
Funding
Abstract
background and purposeThe toll-like receptor TLR4 is involved in neuropathic pain and in drug reward and reinforcement. The opioid inactive isomers (+)-naltrexone and (+)-naloxone act as TLR4 antagonists, reversing neuropathic pain and reducing opioid and cocaine reward and reinforcement. However, how these agents modulate TLR4 signalling is not clear. Here, we have elucidated the molecular mechanism of (+)-naltrexone and (+)-naloxone on TLR4 signalling. EXPERIMENTAL APPROACH: BV-2 mouse microglial cell line, primary rat microglia and primary rat peritoneal macrophages were treated with LPS and TLR4 signalling inhibitors. Effects were measured using Western blotting, luciferase reporter assays, fluorescence microscopy and ELISA KEY
results(+)-Naltrexone and (+)-naloxone were equi-potent inhibitors of the LPS-induced TLR4 downstream signalling and induction of the pro-inflammatory factors NO and TNF-α. Similarly, (+)-naltrexone or (+)-naloxone inhibited production of reactive oxygen species and increased microglial phagocytosis, induced by LPS. However, (+)-naltrexone and (+)-naloxone did not directly inhibit the increased production of IL-1β, induced by LPS. The drug interaction of (+)-naloxone and (+)-naltrexone was additive. (+)-Naltrexone or (+)-naloxone inhibited LPS-induced activation of IFN regulatory factor 3 and production of IFN-β. However, they did not inhibit TLR4 signalling via the activation of either NF-κB, p38 or JNK in these cellular models. CONCLUSIONS AND IMPLICATIONS: (+)-Naltrexone and (+)-naloxone were TRIF-IFN regulatory factor 3 axis-biased TLR4 antagonists. They blocked TLR4 downstream signalling leading to NO, TNF-α and reactive oxygen species. This pattern may explain, at least in part, the in vivo therapeutic effects of (+)-naltrexone and (+)-naloxone.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.