Endogenous opioids modulate the growth of the biliary tree in the course of cholestasis.
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.
Marzioni
Marco
M
Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy. marco.marzioni@tele2.it
Alpini
Gianfranco
G
Saccomanno
Stefania
S
de Minicis
Samuele
S
Glaser
Shannon
S
Francis
Heather
H
Trozzi
Luciano
L
Venter
Juliet
J
Orlando
Fiorenza
F
Fava
Giammarco
G
Candelaresi
Cinzia
C
Macarri
Giampiero
G
Benedetti
Antonio
A
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
D018847:Opioid Peptides; D004744:Enkephalin, Methionine