ArticleNature neuroscience2013
Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl⁻ homeostasis.
Article in Nature neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02992938 (Administration of Acetazolamide to Prevent Remifentanil Induced Hyperalgesia), which is not on this map. Cited by 244 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
Administration of Acetazolamide to Prevent Remifentanil Induced Hyperalgesia: Randomize Double Blind Clinical Trial
Who cites it
244 citing papers in PubMed, 1 synthesis or guideline pooled it, 428 citations in OpenAlex.
- Transcranial Direct Current Stimulation to Improve the Dysfunction of Descending Pain Modulatory System Related to Opioids in Chronic Non-cancer Pain: An Integrative Review of Neurobiology and Meta-Analysis.Frontiers in neuroscience · 2019Pooled it
- Trial
- The efficacy and safety of patient-controlled intravenous analgesia with esketamine after total hip arthroplasty: a randomized controlled trial.BMC anesthesiology · 2025Trial
- Brain organoids as models of extracellular vesicle-mediated human neural communication.Neural regeneration research · 2026Article
- Targeting Spinal Dorsal Horn Sensitisation in Chronic Pain: Mechanisms and Translational Strategies.Neuroscience bulletin · 2026Review
- Article
- The actions of morphine on microglia and the underlying effects on associated adverse effects.Psychopharmacology · 2026Review
- Sex-Specific Mechanisms of Central Sensitization: A Narrative Review of the Neuroimmune Architecture of Chronic Pain.Cureus · 2026Review
- Persistent Mu-Opioid Receptor Dysregulation in a Pain-Facilitatory Brain Region Reinstates Hyperalgesia After Resolution of Opioid-Induced Hyperalgesia.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Review
- Plasma EAAT2 and GABA as candidate biomarkers in males with autism spectrum disorder: an exploratory case-control study with ROC analysis.Scientific reports · 2026Article
- Prenatal maternal infection promotes maternal microchimeric cells to alter infection risk in male offspring.Frontiers in immunology · 2026Article
- Morphine Tolerance Gated through EZH2-Mediated Suppression of Trpc5 in Spinal GABAergic Interneurons in Male Mice.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- 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
- Article
- NLRP3 inflammasome: a key driver of neuroinflammation and a novel therapeutic target for neuropathic pain.Anesthesia and pain medicine · 2025Review
- Effect of esketamine on the ECiScience · 2025Article
- Dexmedetomidine Alleviates Remifentanil-Induced Hyperalgesia in Rats by Modulating the P2 X 4/BDNF Pathway.Neurochemical research · 2025Article
- BDNF Signaling and Pain Modulation.Cells · 2025Review
- Resolvin D1 accelerates resolution of neuroinflammation by inhibiting microglia activation through the BDNF/TrkB signaling pathway.European journal of medical research · 2025Article
184 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
Authors and funding
17 authors at 5 institutions in 2 countries.
Funding
Abstract
A major unresolved issue in treating pain is the paradoxical hyperalgesia produced by the gold-standard analgesic morphine and other opiates. We found that hyperalgesia-inducing treatment with morphine resulted in downregulation of the K(+)-Cl(-) co-transporter KCC2, impairing Cl(-) homeostasis in rat spinal lamina l neurons. Restoring the anion equilibrium potential reversed the morphine-induced hyperalgesia without affecting tolerance. The hyperalgesia was also reversed by ablating spinal microglia. Morphine hyperalgesia, but not tolerance, required μ opioid receptor-dependent expression of P2X4 receptors (P2X4Rs) in microglia and μ-independent gating of the release of brain-derived neurotrophic factor (BDNF) by P2X4Rs. Blocking BDNF-TrkB signaling preserved Cl(-) homeostasis and reversed the hyperalgesia. Gene-targeted mice in which Bdnf was deleted from microglia did not develop hyperalgesia to morphine. However, neither morphine antinociception nor tolerance was affected in these mice. Our findings dissociate morphine-induced hyperalgesia from tolerance and suggest the microglia-to-neuron P2X4-BDNF-KCC2 pathway as a therapeutic target for preventing hyperalgesia without affecting morphine analgesia.
Indexed as
Identifiers
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.