Journal club 2013-05-10

The TGR5 receptor mediates bile acid– induced itch and analgesia

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Farzad Alemi,1 Edwin Kwon,1 Daniel P. Poole,2 TinaMarie Lieu,3 Victoria Lyo,1 Fiore Cattaruzza,1 Ferda Cevikbas,4 Martin Steinhoff,4 Romina Nassini,5 Serena Materazzi,5 Raquel Guerrero-Alba,6 Eduardo Valdez-Morales,6 Graeme S. Cottrell,7 Kristina Schoonjans,8 Pierangelo Geppetti,5 Stephen J. Vanner,6 Nigel W. Bunnett,3 and Carlos U. Corvera1

1Department of Surgery, UCSF, San Francisco, California, USA. 2Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia. 3Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia. 4Department of Dermatology, UCSF, San Francisco, California, USA. 5Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy. 6Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queen’s University, Kingston, Ontario, Canada. 7Department of Pharmacy and Pharmacology, The University of Bath, Bath, United Kingdom. 8Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, School of Life Sciences, Lausanne, Switzerland.

Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symp- toms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cho- lestasis, 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 neu- rons 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.