TY - JOUR
T1 - The TGR5 receptor mediates bile acid-induced itch and analgesia
AU - Alemi, Farzad
AU - Kwon, Edwin
AU - Poole, Daniel P.
AU - Lieu, Tina Marie
AU - Lyo, Victoria
AU - Cattaruzza, Fiore
AU - Cevikbas, Ferda
AU - Steinhoff, Martin
AU - Nassini, Romina
AU - Materazzi, Serena
AU - Guerrero-Alba, Raquel
AU - Valdez-Morales, Eduardo
AU - Cottrell, Graeme S.
AU - Schoonjans, Kristina
AU - Geppetti, Pierangelo
AU - Vanner, Stephen J.
AU - Bunnett, Nigel W.
AU - Corvera, Carlos U.
PY - 2013/4/1
Y1 - 2013/4/1
N2 - 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 leucineenkephalin. 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.
AB - 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 leucineenkephalin. 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.
UR - http://www.scopus.com/inward/record.url?scp=84875848761&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84875848761&partnerID=8YFLogxK
U2 - 10.1172/JCI64551
DO - 10.1172/JCI64551
M3 - Article
C2 - 23524965
AN - SCOPUS:84875848761
VL - 123
SP - 1513
EP - 1530
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 4
ER -