title: Impaired Itching Perception in Murine Models of Cholestasis Is Supported by Dysregulation of GPBAR1 Signaling.
abstract: OBJECTIVE
  In cholestatic syndromes, body accumulation of bile acids is thought to cause itching. However, the mechanisms supporting this effect remain elusive. Recently, GPBAR1 (TGR5) a G-protein coupled receptor has been shown to mediate itching caused by intradermal administration of DCA and LCA. 6α-ethyl-3α, 7α-dihydroxy-24-nor-5β-cholan-23-ol (BAR502) is a non-bile acid dual ligand for FXR and GPBAR1.
  
  
  METHODS
  Cholestasis was induced in wild type and GPBAR1-/- mice by administration of α-naphthyl-isothiocyanate (ANIT) or 17α-ethynylestradiol.
  
  
  RESULTS
  In naïve mice skin application of DCA, TLCA, 6-ECDCA, oleanolic and betulinic acid induces a GPBAR1 dependent pruritogenic response that could be desensitized by re-challenging the mice with the same GPBAR1 agonist. In wild type and GPBAR1-/- mice cholestasis induced by ANIT fails to induce spontaneous itching and abrogates scratching behavior caused by intradermal administration of DCA. In this model, co-treatment with BAR502 increases survival, attenuates serum alkaline phosphatase levels and robustly modulates the liver expression of canonical FXR target genes including OSTα, BSEP, SHP and MDR1, without inducing pruritus. Betulinic acid, a selective GPBAR1 ligand, failed to rescue wild type and GPBAR1-/- mice from ANIT cholestasis but did not induced itching. In the 17α-ethynylestradiol model BAR502 attenuates cholestasis and reshapes bile acid pool without inducing itching.
  
  
  CONCLUSIONS
  The itching response to intradermal injection of GPBAR1 agonists desensitizes rapidly and is deactivated in models of cholestasis, explain the lack of correlation between bile acids levels and itching severity in cholestatic syndromes. In models of non-obstructive cholestasis, BAR502 attenuates liver injury without causing itching.
authors.affiliation: Department of Medicine University of Perugia, Perugia, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cipriani
authors.affiliation: Department of Surgery and Biomedical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.affiliation: Department of Surgery and Biomedical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Amore
authors.affiliation: Department of Surgery and Biomedical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Simonetti
authors.affiliation: Department of Surgery and Biomedical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Antonio Angelo
authors.initials: AA
authors.lastname: De Tursi
authors.affiliation: Department of Surgery and Biomedical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Carino
authors.affiliation: Department of Pharmacy, University of Salerno, Salerno, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Monti
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sepe
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
authors.affiliation: Department of Surgery and Biomedical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000009:adverse effects / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism; D002757:Cholanes / Q000378:metabolism / Q000494:pharmacology; D002779:Cholestasis / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004967:Estrogens / Q000009:adverse effects; D017353:Gene Deletion; D017879:Isothiocyanates / Q000009:adverse effects; D008024:Ligands; D008297:Male; D051379:Mice; D011537:Pruritus / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002757:Cholanes; D004967:Estrogens; D017879:Isothiocyanates; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D000099150:Receptor, Farnesoid X-Activated; C513561:Gpbar1 protein, mouse; C037152:isothiocyanic acid