Impaired Itching Perception in Murine Models of Cholestasis Is Supported by Dysregulation of GPBAR1 Signaling

摘要: Background & Aims 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 mediate itching caused by intradermal administration DCA and LCA. 6α-ethyl-3α, 7α-dihydroxy-24-nor-5β-cholan-23-ol (BAR502) non-bile acid dual ligand for FXR GPBAR1. Methods Cholestasis was induced in wild type GPBAR1-/- mice α-naphthyl-isothiocyanate (ANIT) or 17α-ethynylestradiol. Results. naive skin application DCA, TLCA, 6-ECDCA, oleanolic betulinic induces dependent pruritogenic response that could be desensitized re-challenging with same agonist. In cholestasis ANIT fails induce spontaneous abrogates scratching behavior DCA. model, co-treatment BAR502 increases survival, attenuates serum alkaline phosphatase levels robustly modulates liver expression canonical target genes including OSTα, BSEP, SHP MDR1, without inducing pruritus. Betulinic acid, selective ligand, failed rescue from but did not 17α-ethynylestradiol model reshapes pool itching. Conclusions The injection agonists desensitizes rapidly deactivated models cholestasis, explain lack correlation between severity syndromes. non-obstructive injury causing