ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2013
Blockade of Toll-like receptor 4 attenuates morphine tolerance and facilitates the pain relieving properties of morphine.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 96 papers, 1 of them a synthesis that pooled it.
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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.
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Who cites it
96 citing papers in PubMed, 1 synthesis or guideline pooled it, 217 citations in OpenAlex.
- Opioid peptides in autism spectrum disorder and gluten-free casein-free diet as a therapeutic approach.Metabolic brain disease · 2026Pooled it
- The PPARγ Agonist Pioglitazone Fails to Alter the Abuse Potential of Heroin, But Does Reduce Heroin Craving and Anxiety.Journal of psychoactive drugsTrial
- Spinal NLRP3 blockade reverses morphine-prolonged neuropathic pain and proinflammatory immune actions in prenatal alcohol-exposed male mice.Neuropharmacology · 2026Article
- The neuroimmune-glutamate hypothesis of addiction.Neuroscience and biobehavioral reviews · 2026Review
- The actions of morphine on microglia and the underlying effects on associated adverse effects.Psychopharmacology · 2026Review
- Pharmacogenomic-guided opioid prescribing in hospice: reducing toxicity while maximizing symptom relief.Frontiers in medicine · 2026Review
- Repeat Opioid Use Modulates Microglia Activity and Amyloid Beta Clearance in a Mouse Model of Alzheimer's Disease.bioRxiv : the preprint server for biology · 2025Article
- TLRs/PI3K/AKT1B Signaling Pathway Is Involved in Modulation of Neuroinflammation in the Rat Hippocampus by Alpha-pinene in Morphine-dependent and Withdrawing Rats.Neurochemical research · 2025Article
- Cerebrospinal Fluid Biomarkers in Opioid Dependence: Evidence of Neuroimmune Activation and Ion Composition Changes, Without Alteration in Orexin-A.Addiction biology · 2025Article
- Adolescent morphine exposure does not alter low-dose lipopolysaccharide (LPS)-induced sickness behavior in adult C57/BL6 mice.PloS one · 2025Article
- Alterations in Circular RNAs circOprm1 and circSerpini in the Striatum are Associated with Changes in Spatial Working Memory Performance after Morphine Dependence and Withdrawal in Rats.Neurochemical research · 2024Article
- Immune-mediated impairment of tonic immobility defensive behavior in an experimental model of colonic inflammation.Pflugers Archiv : European journal of physiology · 2024Article
- Targeting exosomal double-stranded RNA-TLR3 signaling pathway attenuates morphine tolerance and hyperalgesia.Cell reports. Medicine · 2024Article
- The Inflammation/NF-κB and BDNF/TrkB/CREB Pathways in the Cerebellum Are Implicated in the Changes in Spatial Working Memory After Both Morphine Dependence and Withdrawal in Rat.Molecular neurobiology · 2024Article
- The effect of cannabinoid type 2 receptor agonist on morphine tolerance.IBRO neuroscience reports · 2024Review
- Screening TLR4 Binding Peptide fromToxins · 2024Article
- Article
- Microglia in morphine tolerance: cellular and molecular mechanisms and therapeutic potential.Frontiers in pharmacology · 2024Review
- Fentanyl enhances immune cell response through TLR4/MD-2 complex.Frontiers in pharmacology · 2024Article
- TLR4 induced TRPM2 mediated neuropathic pain.Frontiers in pharmacology · 2024Review
36 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The ventrolateral periaqueductal gray (vlPAG) is an integral locus for morphine action. Although it is clear that glia contribute to the development of morphine tolerance, to date, the investigation of their role has been limited to spinal and medullary loci. Opioids induce a neuroinflammatory response that opposes acute and long-term analgesia, thereby limiting their efficacy as therapeutic agents. Recent data suggest that the innate immune receptor Toll-like receptor 4 (TLR4), along with its coreceptor myeloid differentiation factor-2 (MD-2), mediates these effects. To date, the brain loci through which TLR4 modulates morphine tolerance have not been identified. We have previously demonstrated that chronic subcutaneous morphine results in tolerance that is accompanied by increases in vlPAG glial cell activity. Using in vivo pharmacological manipulations of vlPAG glia and TLR4 in the adult male rat, we show that intra-vlPAG administration of the general glial cell metabolic inhibitor propentofylline or the astrocyte activity inhibitor fluorocitrate attenuate tolerance to morphine. Characterization of MD-2 expression within the PAG revealed dense MD-2 expression throughout the vlPAG. Further, antagonizing vlPAG TLR4 dose dependently prevented the development of morphine tolerance, and vlPAG microinjections of TLR4 agonists dose dependently produced a "naive" tolerance to subsequent challenge doses of morphine. Finally, using a model of persistent inflammatory pain and pharmacological manipulation of TLR4 we demonstrate that systemic antagonism of TLR4 potentiated acute morphine antihyperalgesia. These results, together, indicate that vlPAG glia regulate morphine tolerance development via TLR4 signaling, and implicate TLR4 as a potential therapeutic target for the treatment of pain.
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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.