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.
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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

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Figure 6

Effects of BAs on scratching behavior in Tgr5-WT, Tgr5-KO, and Tgr5-Tg mice.

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Effects of BAs on scratching behavior in Tgr5-WT, Tgr5-KO, and Tgr5-Tg m...
Results are expressed as the number of scratching events for the indicated time periods. (A and B) Spontaneous scratching in untreated mice. (A) Frequency of spontaneous scratching events during 30-minute intervals over 120 minutes of recording. (B) Frequency of spontaneous scratching events per 60 minutes, averaged over 120 minutes of recording. Tgr5-Tg mice exhibited increased frequency of spontaneous scratching compared with Tgr5-WT and Tgr5-KO mice. (C) Vehicle control (0.9% NaCl, intradermal to the nape of the neck) did not stimulate scratching, although scratching was generally more frequent in Tgr5-Tg mice. (D) DCA (25 μg, intradermal) robustly stimulated scratching in Tgr5-WT mice, and scratching was exacerbated in Tgr5-Tg mice and suppressed in Tgr5-KO mice. (E) DCA (5–25 μg) stimulated dose-dependent scratching in Tgr5-WT mice. (F and G) TLCA and OA (25 μg) stimulated scratching in Tgr5-WT mice, which was markedly attenuated in Tgr5-KO mice. (H) UDCA (25 μg) had a small stimulatory effect that was not different among Tgr5-Tg, Tgr5-KO, and Tgr5-WT mice. (I) Histamine (50 μg) stimulated scratching to a similar extent in Tgr5-Tg, Tgr5-KO, and Tgr5-WT mice. (J) Summarized results showing the frequency of scratching events during the first 60 minutes after injection. *P < 0.05, **P < 0.01 vs. Tgr5-WT; #P < 0.05 vs. 5 μg DCA; ANOVA and Student-Newman-Keuls post-hoc test. n is indicated.