title: Potentiation of the transient receptor potential vanilloid 1 channel contributes to pruritogenesis in a rat model of liver disease.
abstract: Persistent pruritus is a common disabling dermatologic symptom associated with different etiologic factors. These include primary skin conditions, as well as neuropathic, psychogenic, or systemic disorders like chronic liver disease. Defective clearance of potential pruritogenic substances that activate itch-specific neurons innervating the skin is thought to contribute to cholestatic pruritus. However, because the underlying disease-specific pruritogens and itch-specific neuronal pathways and mechanism(s) are unknown, symptomatic therapeutic intervention often leads to no or only limited success. In the current study, we aimed to first validate rats with bile duct ligation (BDL) as a model for hepatic pruritus and then to evaluate the contribution of inflammation, peripheral neuronal sensitization, and specific signaling pathways and subpopulations of itch-responsive neurons to scratching behavior and thermal hypersensitivity. Chronic BDL rats displayed enhanced scratching behavior and thermal hyperalgesia indicative of peripheral neuroinflammation. BDL-induced itch and hypersensitivity involved a minor contribution of histaminergic/serotonergic receptors, but significant activation of protein-activated receptor 2 (PAR2) receptors, prostaglandin PGE2 formation, and potentiation of transient receptor potential vanilloid 1 (TRPV1) channel activity. The sensitization of dorsal root ganglion nociceptors in BDL rats was associated with increased surface expression of PAR2 and TRPV1 proteins and an increase in the number of PAR2- and TRPV1-expressing peptidergic neurons together with a shift of TRPV1 receptor expression to medium sized dorsal root ganglion neurons. These results suggest that pruritus and hyperalgesia in chronic cholestatic BDL rats are associated with neuroinflammation and involve PAR2-induced TRPV1 sensitization. Thus, pharmacological modulation of PAR2 and/or TRPV1 may be a valuable therapeutic approach for patients with chronic liver pruritus refractory to conventional treatments.
authors: Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
authors: Majedeline
authors: M
authors: Belghiti
authors: Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
authors: Judith
authors: J
authors: Estévez-Herrera
authors: Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
authors: Carla
authors: C
authors: Giménez-Garzó
authors: Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
authors: Alba
authors: A
authors: González-Usano
authors: Fundación Investigación Hospital Clínico de Valencia, INCLIVA, 46010 Valencia, Spain.
authors: Carmina
authors: C
authors: Montoliu
authors: Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Spain.
authors: Antonio
authors: A
authors: Ferrer-Montiel
authors: Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
authors: Vicente
authors: V
authors: Felipo
authors: Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain; Leibniz-Institut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), 13125 Berlin, Germany. Electronic address: planells-cases@fmp-berlin.de.
authors: Rosa
authors: R
authors: Planells-Cases
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D002779:Cholestasis / Q000378:metabolism; D002908:Chronic Disease; D006358:Hot Temperature; D006930:Hyperalgesia / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008407:Mast Cells / Q000473:pathology; D008856:Microscopy, Fluorescence / Q000379:methods; D008959:Models, Neurological; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D011537:Pruritus / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2 / Q000378:metabolism; D015398:Signal Transduction; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D044464:Receptor, PAR-2; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat