Impaired Itching Perception in Murine Models of Cholestasis Is Supported by Dysregulation of GPBAR1 Signaling
Sabrina Cipriani1☯, Barbara Renga2☯, Claudio D’Amore2, Michele Simonetti2, Antonio
Angelo De Tursi2, Adriana Carino2, Maria Chiara Monti3, Valentina Sepe4,
Angela Zampella4, Stefano Fiorucci2*
1 Department of Medicine University of Perugia, Perugia, Italy, 2 Department of Surgery and Biomedical
Sciences, University of Perugia, Perugia, Italy, 3 Department of Pharmacy, University of Salerno, Salerno,
Italy, 4 Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Abstract
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 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-naphthylisothiocyanate (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-challengingthe mice with the same GPBAR1 agonist. In wild type and GPBAR1-/- mice cholestasisinduced 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.
