Endogenous opioids modulate the growth of the biliary tree in the course of cholestasis

Background & Aims: 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 8 opioid receptor (OR), mu OR, and kappa OR 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. delta OR activation strongly diminished the proliferative and functional response of cholangiocytes to cholestasis, whereas mu OR resulted in a slight increase in cell growth. The delta OR signal is mediated by the IP3/CamKII alpha/PKC alpha pathway, which inhibits the cAMP/PKA/ERK1/2/AKT cascade. In contrast, mu OR activation stimulates the cAMP/PKA/ERK1/2/AKT cascade but does not affect the IP3/CamKII alpha/PKC alpha 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 delta OR expressed by cholangiocytes.