ArticleBrain, behavior, and immunity2008
Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia.
Article in Brain, behavior, and immunity, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 155 papers, 1 of them a synthesis that pooled it.
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.
The trial behind it
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
155 citing papers in PubMed, 1 synthesis or guideline pooled it, 301 citations in OpenAlex.
- Effects of opioids on immunologic parameters that are relevant to anti-tumour immune potential in patients with cancer: a systematic literature review.British journal of cancer · 2014Pooled it
- Effects of Ibudilast on the Subjective, Reinforcing, and Analgesic Effects of Oxycodone in Recently Detoxified Adults with Opioid Dependence.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2017Trial
- Ultralow Dose of Naloxone as an Adjuvant to Intrathecal Morphine Infusion Improves Perceived Quality of Sleep but Fails to Alter Persistent Pain: A Randomized, Double-blind, Controlled Study.The Clinical journal of pain · 2015Trial
- Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice.Proceedings of the National Academy of Sciences of the United States of America · 2012Trial
- Gabapentin improves cold-pressor pain responses in methadone-maintained patients.Drug and alcohol dependence · 2010Trial
- Opioid treatment of experimental pain activates nuclear factor-κB.Journal of opioid managementTrial
- 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
- Alpha-pinene modulates hippocampal MAPKs/c-Fos pathways during morphine dependence and withdrawal in rats.Psychopharmacology · 2026Article
- Animal Models of Prenatal Opioid Exposure: Insights into Impaired Neurodevelopment.Advances in experimental medicine and biology · 2026Review
- BTP2, a store-operated calcium channel inhibitor, attenuates morphine antinociceptive tolerance in rats.Frontiers in neuroscience · 2026Article
- Narrative review of the scientific and methodological explanations for 101 mechanisms of opioid tolerance.Pain reports · 2025Article
- Molecular Mechanisms Underlying Burn-Injury Induced Pain: From Inflammation to Epigenetics.Military medicine · 2025Review
- NETs activate the GAS6-AXL-NLRP3 axis in macrophages to drive morphine tolerance.Cell communication and signaling : CCS · 2025Article
- Methadone and Buprenorphine as Medication for Addiction Treatment Diversely Affect Inflammation and Craving Depending on Their Doses.Pharmacy (Basel, Switzerland) · 2025Article
- Cellular senescence in the innervated niche modulates cancer-associated pain: an emerging therapeutic target?Frontiers in immunology · 2025Review
- Nanotechnology-Enhanced Naloxone and Alternative Treatments for Opioid Addiction.ACS pharmacology & translational science · 2024Review
- Methadone Requires the Co-Activation of μ-Opioid and Toll-Like-4 Receptors to Produce Extracellular DNA Traps in Bone-Marrow-Derived Mast Cells.International journal of molecular sciences · 2024Article
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95 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 3 countries.
Funding
Abstract
Spinal proinflammatory cytokines are powerful pain-enhancing signals that contribute to pain following peripheral nerve injury (neuropathic pain). Recently, one proinflammatory cytokine, interleukin-1, was also implicated in the loss of analgesia upon repeated morphine exposure (tolerance). In contrast to prior literature, we demonstrate that the action of several spinal proinflammatory cytokines oppose systemic and intrathecal opioid analgesia, causing reduced pain suppression. In vitro morphine exposure of lumbar dorsal spinal cord caused significant increases in proinflammatory cytokine and chemokine release. Opposition of analgesia by proinflammatory cytokines is rapid, occurring < or =5 min after intrathecal (perispinal) opioid administration. We document that opposition of analgesia by proinflammatory cytokines cannot be accounted for by an alteration in spinal morphine concentrations. The acute anti-analgesic effects of proinflammatory cytokines occur in a p38 mitogen-activated protein kinase and nitric oxide dependent fashion. Chronic intrathecal morphine or methadone significantly increased spinal glial activation (toll-like receptor 4 mRNA and protein) and the expression of multiple chemokines and cytokines, combined with development of analgesic tolerance and pain enhancement (hyperalgesia, allodynia). Statistical analysis demonstrated that a cluster of cytokines and chemokines was linked with pain-related behavioral changes. Moreover, blockade of spinal proinflammatory cytokines during a stringent morphine regimen previously associated with altered neuronal function also attenuated enhanced pain, supportive that proinflammatory cytokines are importantly involved in tolerance induced by such regimens. These data implicate multiple opioid-induced spinal proinflammatory cytokines in opposing both acute and chronic opioid analgesia, and provide a novel mechanism for the opposition of acute opioid analgesia.
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What OpenQuestion holds
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.