ArticleProceedings of the National Academy of Sciences of the United States of America2012
Morphine activates neuroinflammation in a manner parallel to endotoxin.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 270 papers.
What it found
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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.
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Who cites it
270 citing papers in PubMed, 503 citations in OpenAlex.
- Spinal neuronal TLR4-induced enhancement of nociceptive signals contributes to myocardial ischemia/reperfusion injury.Basic research in cardiology · 2026Article
- Preliminary evidence of neuroimmune system disruption in opioid use disorder: Findings from a pilot PET TSPO imaging study.Brain, behavior, & immunity - health · 2026Article
- The neuroimmune-glutamate hypothesis of addiction.Neuroscience and biobehavioral reviews · 2026Review
- Adolescent prefrontal and amygdala molecular signatures of perinatal morphine versus buprenorphine exposure in mice.Neurotoxicology · 2026Article
- The role of persistent inflammation in failed recovery after perinatal brain injury: is resolution the cure?Journal of neuroinflammation · 2026Review
- A tailored pain self-management intervention for patients with cirrhosis is acceptable and improves pain control.Hepatology communications · 2026Article
- Substance abuse and inflammation: consequences beyond the brain.Trends in immunology · 2026Review
- Morphine and methamphetamine trigger divergent post-transcriptional neuroimmune landscapes in the dorsal striatum.bioRxiv : the preprint server for biology · 2026Article
- Animal Models of Prenatal Opioid Exposure: Insights into Impaired Neurodevelopment.Advances in experimental medicine and biology · 2026Review
- Article
- BTP2, a store-operated calcium channel inhibitor, attenuates morphine antinociceptive tolerance in rats.Frontiers in neuroscience · 2026Article
- Single-cell transcriptomics reveals probiotic reversal of neonatal morphine-induced gene disruptions underlying adolescent pain hypersensitivity.Communications biology · 2025Article
- Prenatal alcohol exposure promotes nerve injury-induced pathological pain following morphine treatment via NLRP3-mediated peripheral and central proinflammatory immune actions.Brain, behavior, and immunity · 2025Article
- Novel neurotherapeutic targets for substance use disorders: Neuroplasticity, neuroinflammation, gasotransmitters and non-canonical organ systems.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
- Article
- Unveiling the therapeutic potential of octreotide in treating morphine dependence.Scientific reports · 2025Article
- Pharmacokinetic analysis of morphine-3-glucuronide after acute morphine intravenous bolus administration to rats with traumatic brain injury.The Journal of pharmacology and experimental therapeutics · 2025Article
- Potential roles for microglia in drug addiction: Adolescent neurodevelopment and beyond.Journal of neuroimmunology · 2025Review
- Review
- Prefrontal cortical microglial transcriptome relates to mouse offspring executive function deficits after perinatal opioid exposure in a sex-dependent manner.Brain, behavior, and immunity · 2025Article
210 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
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.
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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.