ArticleTranslational psychiatry2014
Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation.
Article in Translational psychiatry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 94 citations in OpenAlex.
- Cutaneous Allodynia Associated With GLP-1RA Tirzepatide for Weight Management: A Case Series.The American journal of case reports · 2026Article
- Astrocytes and Astrocyte-Derived Extracellular Conduits in Opiate-Mediated Neurological Disorders.Cells · 2025Review
- Mu-Opioid Receptor (MOR) Dependence of Pain in Chemotherapy-Induced Peripheral Neuropathy.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Personalized anesthesia and precision medicine: a comprehensive review of genetic factors, artificial intelligence, and patient-specific factors.Frontiers in medicine · 2024Review
- Targeting Peripheral μ-opioid Receptors or μ-opioid Receptor-Expressing Neurons Does not Prevent Morphine-induced Mechanical Allodynia and Anti-allodynic Tolerance.Neuroscience bulletin · 2023Article
- Non-Peptide Opioids Differ in Effects on Mu-Opioid (MOP) and Serotonin 1A (5-HTMolecules (Basel, Switzerland) · 2022Article
- Review
- Molecular Mechanism of Neuroprotective Effect of Melatonin on Morphine Addiction and Analgesic Tolerance: an Update.Molecular neurobiology · 2021Review
- Addressing opioid tolerance and opioid-induced hypersensitivity: Recent developments and future therapeutic strategies.Pharmacology research & perspectives · 2021Review
- Comparison of morphine, oxycodone and the biased MOR agonist SR-17018 for tolerance and efficacy in mouse models of pain.Neuropharmacology · 2021Article
- Postoperative cognitive dysfunction is made persistent with morphine treatment in aged rats.Neurobiology of aging · 2021Article
- Opioid-Induced Tolerance and Hyperalgesia.CNS drugs · 2019Review
- Role of Nociceptor Toll-like Receptor 4 (TLR4) in Opioid-Induced Hyperalgesia and Hyperalgesic Priming.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
- Cytokines in Pain: Harnessing Endogenous Anti-Inflammatory Signaling for Improved Pain Management.Frontiers in immunology · 2019Review
- Morphine-induced hyperalgesia involves mu opioid receptors and the metabolite morphine-3-glucuronide.Scientific reports · 2017Article
- Involvement of delta opioid receptors in alcohol withdrawal-induced mechanical allodynia in male C57BL/6 mice.Drug and alcohol dependence · 2016Article
- Blockade of Toll-Like Receptors (TLR2, TLR4) Attenuates Pain and Potentiates Buprenorphine Analgesia in a Rat Neuropathic Pain Model.Neural plasticity · 2016Article
- Review
- Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chronic morphine therapy has been associated with paradoxically increased pain. Codeine is a widely used opioid, which is metabolized to morphine to elicit analgesia. Prolonged morphine exposure exacerbates pain by activating the innate immune toll-like receptor-4 (TLR4) in the central nervous system. In silico docking simulations indicate codeine also docks to MD2, an accessory protein for TLR4, suggesting potential to induce TLR4-dependent pain facilitation. We hypothesized codeine would cause TLR4-dependent hyperalgesia/allodynia that is disparate from its opioid receptor-dependent analgesic rank potency. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests at days 0, 3 and 5 in mice receiving intraperitoneal equimolar codeine (21 mg kg(-1)), morphine (20 mg kg(-1)) or saline, twice daily. This experiment was repeated in animals with prior partial nerve injury and in TLR4 null mutant mice. Interventions with interleukin-1 receptor antagonist (IL-1RA) and glial-attenuating drug ibudilast were assessed. Analyses of glial activation markers (glial fibrillary acid protein and CD11b) in neuronal tissue were conducted at the completion of behavioural testing. Despite providing less acute analgesia (P=0.006), codeine induced similar hotplate hyperalgesia to equimolar morphine vs saline (-9.5 s, P<0.01 and -7.3 s, P<0.01, respectively), suggesting codeine does not rely upon conversion to morphine to increase pain sensitivity. This highlights the potential non-opioid receptor-dependent nature of codeine-enhanced pain sensitivity-although the involvement of other codeine metabolites cannot be ruled out. IL-1RA reversed codeine-induced hyperalgesia (P<0.001) and allodynia (P<0.001), and TLR4 knock-out protected against codeine-induced changes in pain sensitivity. Glial attenuation with ibudilast reversed codeine-induced allodynia (P<0.001), and thus could be investigated further as potential treatment for codeine-induced pain enhancement.
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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.