ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2012
Opioid activation of toll-like receptor 4 contributes to drug reinforcement.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 175 papers.
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Who cites it
175 citing papers in PubMed, 343 citations in OpenAlex.
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- The actions of morphine on microglia and the underlying effects on associated adverse effects.Psychopharmacology · 2026Review
- Substance abuse and inflammation: consequences beyond the brain.Trends in immunology · 2026Review
- Salivary transcriptomic study to understand the molecular effects of feeding dysregulation in opioid-exposed neonates born late preterm.Journal of neonatal-perinatal medicine · 2026Article
- Kratom (Molecules (Basel, Switzerland) · 2026Article
- Opioid Receptors in Psychedelia: Indirect Serotonergic Modulation of Direct KOR Activation by Salvinorin A.Biomedicines · 2026Review
- Repeated fentanyl abstinence intensifies opioid withdrawal and induces a proinflammatory state in striatal microglia.Psychopharmacology · 2026Article
- Animal Models of Prenatal Opioid Exposure: Insights into Impaired Neurodevelopment.Advances in experimental medicine and biology · 2026Review
- Immunosuppressant treatment reduces cocaine-induced behavioral sensitization in mice.Frontiers in pharmacology · 2026Article
- Alternating self-administration sessions of cocaine and heroin impact drug-related motivation and vocalisations in rats.Psychopharmacology · 2025Article
- The placenta as a window into neonatal brain injury.Seminars in perinatology · 2025Review
- 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
- Repeated fentanyl abstinence intensifies opioid withdrawal and induces a proinflammatory state in striatal microglia.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
- Microbiome-derived metabolites in substance use disorders: Mechanisms and implications.Annals of the New York Academy of Sciences · 2025Review
- Potential roles for microglia in drug addiction: Adolescent neurodevelopment and beyond.Journal of neuroimmunology · 2025Review
- Hyperbaric oxygen treatment attenuates naloxone-precipitated opioid withdrawal behaviors and alters microglial activity in male and female mice.Scientific reports · 2025Article
- Ibudilast-Mediated Suppression of Neuronal TLR4 in the Prefrontal Cortex Mitigates Methamphetamine-Induced Neuroinflammation and Addictive Behaviours.Addiction biology · 2025Article
115 more citing papers are in PubMed but not listed here.
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Authors and funding
26 authors at 8 institutions in 3 countries.
Funding
Abstract
Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4(-/-) mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system that amplifies opioid-induced elevations in extracellular dopamine levels, therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward.
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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.