ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2017
Toll-like Receptor 4 Mediates Morphine-Induced Neuroinflammation and Tolerance via Soluble Tumor Necrosis Factor Signaling.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers.
What it found
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Who cites it
91 citing papers in PubMed, 134 citations in OpenAlex.
- 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
- Deciphering the impact of genetic variants on vulnerability to Opioid Use Disorder.Frontiers in cellular neuroscience · 2026Article
- Narrative review of the scientific and methodological explanations for 101 mechanisms of opioid tolerance.Pain reports · 2025Article
- Lovastatin Suppresses Morphine-Induced Inflammation and Cell Death in Pheochromocytoma-Like Neural Cells (PC12).Asian Pacific journal of cancer prevention : APJCP · 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
- Article
- Cerebrospinal Fluid Biomarkers in Opioid Dependence: Evidence of Neuroimmune Activation and Ion Composition Changes, Without Alteration in Orexin-A.Addiction biology · 2025Article
- Increased LPS-induced fever and sickness behavior in adult male and female rats perinatally exposed to morphine.Brain, behavior, and immunity · 2025Article
- Pathophysiology and management of burn injury-induced pain.Burns open : an international open access journal for burn injuries · 2025Article
- Faecal Microbiota Transplantation Modulates Morphine Addictive-Like Behaviours Through Hippocampal Metaplasticity.Addiction biology · 2025Article
- Microvascular Dysfunction, Mitochondrial Reprogramming, and Inflammasome Activation as Critical Regulators of Ischemic Stroke Severity Induced by Chronic Exposure to Prescription Opioids.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Neurobiological intersections of stress and substance use disorders.Frontiers in neuroscience · 2025Review
- Molecular and cellular basis of mu-opioid receptor signaling: mechanisms underlying tolerance and dependence development.Frontiers in neuroscience · 2025Review
- Inflammatory and chemotactic signals of the brainstem solitary tract mediate the morphine exacerbation of impaired reflex chronotropism in septic rats.Frontiers in pharmacology · 2025Article
- Adolescent morphine exposure does not alter low-dose lipopolysaccharide (LPS)-induced sickness behavior in adult C57/BL6 mice.PloS one · 2025Article
- YTHDF1 in periaqueductal gray inhibitory neurons contributes to morphine withdrawal responses in mice.BMC medicine · 2024Article
- The effect of cannabinoid type 2 receptor agonist on morphine tolerance.IBRO neuroscience reports · 2024Review
- Microglia in neuroimmunopharmacology and drug addiction.Molecular psychiatry · 2024Review
- Promising immunomodulators for management of substance and alcohol use disorders.Expert opinion on pharmacotherapy · 2024Review
31 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Opioid tolerance and the potential for addiction is a significant burden associated with pain management, yet its precise underlying mechanism and prevention remain elusive. Immune signaling contributes to the decreased efficacy of opioids, and we recently demonstrated that Toll-like receptor 4 (TLR4)-mediated neuroinflammation in the periaqueductal gray (PAG) drives tolerance. Tumor necrosis factor (TNF), a product of TLR4 signaling, promotes inflammation and facilitates glutamatergic signaling, key components of opioid tolerance. Therefore, we hypothesize that TLR4-mediated opioid tolerance requires TNF signaling. By expression of a dominant-negative TNF peptide via lentiviral vector injection in rat PAG to sequester soluble TNF (solTNF), we demonstrate that solTNF mediates morphine tolerance induced by TLR4 signaling, stimulates neuroinflammation (increased IL-1β and TLR4 mRNA), and disrupts glutamate reuptake (decreased GLT-1 and GLAST mRNA). We further demonstrate the efficacy of the brain-permeant PEGylated version of the anti-solTNF peptide, XPro1595, injected systemically, to normalize morphine-induced CNS neuroinflammation and morphine- and endotoxin-induced changes in glutamate transport, effectively preserving the efficacy of morphine analgesia and eliminating tolerance. Our findings provide a novel pharmacological target for the prevention of opioid-induced immune signaling, tolerance, and addiction.
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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.