title: Endogenous opioids modulate the growth of the biliary tree in the course of cholestasis.
abstract: OBJECTIVE
  There is poor knowledge on the factors that modulate the growth of cholangiocytes, the epithelial cell target of cholangiopathies, which are diseases leading to progressive loss of bile ducts and liver failure. Endogenous opioids are known to modulate cell growth. In the course of cholestasis, the opioidergic system is hyperactive, and in cholangiocytes a higher expression of opioid peptide messenger RNA has been described. This study aimed to verify if such events affect the cholangiocyte proliferative response to cholestasis.
  
  
  METHODS
  The presence of the delta opioid receptor (OR), muOR, and kappaOR was evaluated. The effects on cholangiocyte proliferation of the in vitro and in vivo exposure to their selective agonists, together with the intracellular signals, were then studied. The effects of the OR antagonist naloxone on cell growth were also tested both in vivo and in vitro.
  
  
  RESULTS
  Cholangiocytes express all 3 receptors studied. deltaOR activation strongly diminished the proliferative and functional response of cholangiocytes to cholestasis, whereas muOR resulted in a slight increase in cell growth. The deltaOR signal is mediated by the IP3/CamKIIalpha/PKCalpha pathway, which inhibits the cAMP/PKA/ERK1/2/AKT cascade. In contrast, muOR activation stimulates the cAMP/PKA/ERK1/2/AKT cascade but does not affect the IP3/CamKIIalpha/PKCalpha pathway. The blockage of endogenous opioid peptides by naloxone further enhanced cholangiocyte growth both in vivo and in vitro.
  
  
  CONCLUSIONS
  The increase in opioid peptide synthesis in the course of cholestasis aims to limit the excessive growth of the biliary tree in the course of cholestasis by the interaction with the deltaOR expressed by cholangiocytes.
authors.affiliation: Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy. marco.marzioni@tele2.it
authors.forename: Marco
authors.initials: M
authors.lastname: Marzioni
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
authors.forename: Stefania
authors.initials: S
authors.lastname: Saccomanno
authors.forename: Samuele
authors.initials: S
authors.lastname: de Minicis
authors.forename: Shannon
authors.initials: S
authors.lastname: Glaser
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
authors.forename: Luciano
authors.initials: L
authors.lastname: Trozzi
authors.forename: Juliet
authors.initials: J
authors.lastname: Venter
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Orlando
authors.forename: Giammarco
authors.initials: G
authors.lastname: Fava
authors.forename: Cinzia
authors.initials: C
authors.lastname: Candelaresi
authors.forename: Giampiero
authors.initials: G
authors.lastname: Macarri
authors.forename: Antonio
authors.initials: A
authors.lastname: Benedetti
mesh_terms: D000818:Animals; D001659:Biliary Tract / Q000166:cytology* / Q000254:growth & development; D049109:Cell Proliferation; D002478:Cells, Cultured; D002779:Cholestasis / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004744:Enkephalin, Methionine / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D018847:Opioid Peptides / Q000378:metabolism*; D011336:Probability; D011863:Radioimmunoassay; D051381:Rats; D011916:Rats, Inbred F344; D012680:Sensitivity and Specificity; D015398:Signal Transduction
chemical_list: D018847:Opioid Peptides; D004744:Enkephalin, Methionine