The TGR5 receptor mediates bile acid-induced itch and analgesia

The liver secretes bile acids to aid in the digestion of fats. Cholestasis is a condition in which the bile flow from the liver to the duodenum is impeded. Patients with the disease exhibit itchiness (pruritis) and cannot sense pain (analgesia). The molecular mechanisms mediating these effects are unknown. Carlos Corvera of UCSF and Nigel Bunnett of Monash University discuss their study demonstrating that bile acids cause itch and analgesia by activating the TGR5 receptor in neurons. Highlights:

  • TGR5 is expressed in neurons in mouse dorsal root ganglia and spinal cord, which transmit itch and pain signals.
  • Stimulation of TGR5 induced the release of itch and analgesia transmitting molecules, including gastrin-releasing peptide and leucine-enkephalin.
  • Intradermal injection of bile acids stimulated scratching behavior that was TGR5-dependent.
  • Bile acids activate TGR5 on sensory nerves to transmit itch and analgesia, suggesting that these mechanisms contribute to pruritus and analgesia during cholestatic liver diseases.

Published March 25, 2013, by The JCI

Related articles

The TGR5 receptor mediates bile acid–induced itch and analgesia
Farzad Alemi, … , Nigel W. Bunnett, Carlos U. Corvera
Farzad Alemi, … , Nigel W. Bunnett, Carlos U. Corvera
Published March 25, 2013
Citation Information: J Clin Invest. 2013;123(4):1513-1530. https://doi.org/10.1172/JCI64551.
View: Text | PDF
Research Article Hepatology

The TGR5 receptor mediates bile acid–induced itch and analgesia

Abstract

Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symptoms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cholestasis, cause itch and analgesia by activating the GPCR TGR5. TGR5 was detected in peptidergic neurons of mouse dorsal root ganglia and spinal cord that transmit itch and pain, and in dermal macrophages that contain opioids. Bile acids and a TGR5-selective agonist induced hyperexcitability of dorsal root ganglia neurons and stimulated the release of the itch and analgesia transmitters gastrin-releasing peptide and leucine-enkephalin. Intradermal injection of bile acids and a TGR5-selective agonist stimulated scratching behavior by gastrin-releasing peptide– and opioid-dependent mechanisms in mice. Scratching was attenuated in Tgr5-KO mice but exacerbated in Tgr5-Tg mice (overexpressing mouse TGR5), which exhibited spontaneous pruritus. Intraplantar and intrathecal injection of bile acids caused analgesia to mechanical stimulation of the paw by an opioid-dependent mechanism. Both peripheral and central mechanisms of analgesia were absent from Tgr5-KO mice. Thus, bile acids activate TGR5 on sensory nerves, stimulating the release of neuropeptides in the spinal cord that transmit itch and analgesia. These mechanisms could contribute to pruritus and painless jaundice that occur during cholestatic liver diseases.

Authors

Farzad Alemi, Edwin Kwon, Daniel P. Poole, TinaMarie Lieu, Victoria Lyo, Fiore Cattaruzza, Ferda Cevikbas, Martin Steinhoff, Romina Nassini, Serena Materazzi, Raquel Guerrero-Alba, Eduardo Valdez-Morales, Graeme S. Cottrell, Kristina Schoonjans, Pierangelo Geppetti, Stephen J. Vanner, Nigel W. Bunnett, Carlos U. Corvera

×
Advertisement