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 8

Peripheral mechanisms of BA- and TGR5-induced mechanical analgesia and edema in Tgr5-WT and Tgr5-KO mice.

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Peripheral mechanisms of BA- and TGR5-induced mechanical analgesia and e...
Test agents were injected into the plantar surface of the hind paw. Responses to stimulation of the plantar surface of the paw with von Frey filaments of graded stiffness and paw thickness were recorded. Results are expressed as percent basal value. An increased von Frey response indicates that a stiffer filament was required to induce withdrawal (mechanical analgesia), whereas a decreased response indicates that a less stiff filament was required to induce withdrawal (mechanical hyperalgesia). (A) Intraplantar injection of DCA (12.5–125 μg) or capsaicin (5 μg) increased paw thickness in Tgr5-WT mice, indicative of inflammatory edema. (B) Intraplantar DCA (25 μg), but not UDCA (25 μg), caused analgesia, whereas capsaicin (5 μg) caused hyperalgesia, in Tgr5-WT mice. (C) Intraplantar DCA (12.5, 25, 37.5, and 125 μg) stimulated dose-dependent analgesia measured at 3 hours in Tgr5-WT mice. (D) Intraplantar DCA (25 μg) caused analgesia in Tgr5-WT, but not Tgr5-KO, mice. (E and F) TLCA and OA (25 μg) caused analgesia in Tgr5-WT, but not Tgr5-KO, mice. (G) Naloxone or vehicle control was administered by intraplantar injection 2 hours after intraplantar injection of DCA (25 μg) to Tgr5-WT mice. Naloxone rapidly reversed the mechanical analgesia. *P < 0.05, **P < 0.01 vs. respective vehicle control (A, B, and G) or vs. Tgr5-KO (D, E, and F); ANOVA and Student-Newman-Keuls (A and B) or unpaired t test (D–F, and G). n is indicated.