ArticleThe Journal of clinical investigation2013
The TGR5 receptor mediates bile acid-induced itch and analgesia.
Article in The Journal of clinical investigation, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 173 papers, 2 of them syntheses that pooled it.
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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.
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Who cites it
173 citing papers in PubMed, 2 syntheses or guidelines pooled it, 365 citations in OpenAlex.
- Combination therapy of obeticholic acid and ursodeoxycholic acid in patients with primary biliary cholangitis who respond incompletely to ursodeoxycholic acid: a systematic review.European journal of gastroenterology & hepatology · 2020Pooled it
- Cholestatic pruritus: Emerging mechanisms and therapeutics.Journal of the American Academy of Dermatology · 2019Pooled it
- Artificial Liver Support Effectively Removes Immunosuppressive Bile Acids From Circulation in Patients With Severe Liver Failure: A Proof of Concept Study.Critical care explorations · 2026Trial
- Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of INT-787, a Novel Farnesoid X Receptor Agonist, in Healthy Volunteers: A Phase 1 Trial.Clinical and translational science · 2025Trial
- Trial
- Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Non-Bile Acid FXR Agonist Tropifexor (LJN452) in Healthy Volunteers.Clinical pharmacology in drug development · 2020Trial
- Bile acids as a "new hormone" in aging-related liver disease.Life medicine · 2026Review
- Pruritus is common in primary sclerosing cholangitis, persists over time, and its intensity is associated with disease severity: a multicentre, prospective observational study.Hepatology (Baltimore, Md.) · 2026Observational
- Liver-nervous system axis: pathways, dysregulation, and translational perspectives.Journal of neuroinflammation · 2026Review
- Review
- Role and progression of bile acid metabolism in mediating Th17/Treg homeostasis in inflammatory bowel disease.iScience · 2026Review
- From neuroimmune circuits to targeted therapy of chronic pruritus.Pharmacological reviews · 2026Review
- Microbially produced bile acids are associated with increased IgG autoantibodies and poorer mental wellbeing in fibromyalgia.Scientific reports · 2026Article
- A novel TGR5 agonist Sauchinone ameliorates IMQ induced murine psoriasis by regulating macrophage polarization.Journal of advanced research · 2026Article
- From chemical composition to clinical application: the value of bile-based traditional Chinese medicines in the treatment of liver diseases.Frontiers in pharmacology · 2026Review
- Mapping the gut microbiota-diabetic peripheral neuropathy research landscape: a bibliometric analysis of emerging trends and translational frontiers.Frontiers in endocrinology · 2026Article
- Obeticholic acid as an index farnesoid X receptor scaffold in metabolic dysfunction-associated steatohepatitis: a testable model for efficacy-liability separation and biomarker interpretation.Frontiers in pharmacology · 2026Article
- Regulation of bile acids homeostasis: a feasible and versatile way to treat or diagnose liver disorders.Frontiers in nutrition · 2026Review
- The role of bile acid-activated receptor TGR5 in inflammation and liver diseases.Frontiers in physiology · 2026Review
- The role of gut microbiota in neuropathic pain: insights into immune mechanisms.The journal of headache and pain · 2025Review
113 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 6 institutions in 5 countries.
Funding
Abstract
Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symptoms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cholestasis, cause itch and analgesia by activating the GPCR TGR5. TGR5 was detected in peptidergic neurons of mouse dorsal root ganglia and spinal cord that transmit itch and pain, and in dermal macrophages that contain opioids. Bile acids and a TGR5-selective agonist induced hyperexcitability of dorsal root ganglia neurons and stimulated the release of the itch and analgesia transmitters gastrin-releasing peptide and leucine-enkephalin. Intradermal injection of bile acids and a TGR5-selective agonist stimulated scratching behavior by gastrin-releasing peptide- and opioid-dependent mechanisms in mice. Scratching was attenuated in Tgr5-KO mice but exacerbated in Tgr5-Tg mice (overexpressing mouse TGR5), which exhibited spontaneous pruritus. Intraplantar and intrathecal injection of bile acids caused analgesia to mechanical stimulation of the paw by an opioid-dependent mechanism. Both peripheral and central mechanisms of analgesia were absent from Tgr5-KO mice. Thus, bile acids activate TGR5 on sensory nerves, stimulating the release of neuropeptides in the spinal cord that transmit itch and analgesia. These mechanisms could contribute to pruritus and painless jaundice that occur during cholestatic liver diseases.
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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.