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 10

Hypothesized mechanisms of BA- and TGR5-induced itch and analgesia.

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Hypothesized mechanisms of BA- and TGR5-induced itch and analgesia. (A) ...
(A) Mechanisms of itch. BAs in the skin activate TGR5 on sensory nerve endings (i), which increases neuronal excitability and stimulates release of unknown transmitters from the central projections of sensory nerves in dorsal horn of the spinal cord (ii). The transmitters induce release of GRP (iii) and opioids (iv) from spinal neurons. GRP activates GRPR and opioids activate the MOR1D/GRPR heterodimer on itch-selective spinal neurons. Activated GRPR induces itch (v). (B) Mechanisms of analgesia. BAs in the skin activate TGR5 on dermal macrophages (i) to stimulate release of opioids that activate MORs and δ-opioid receptors (DOR) on sensory nerve endings to induce peripheral mechanisms of analgesia (ii). BAs in the spinal cord activate TGR5 on spinal neurons (iii) to stimulate release of opioids that activate MOR1 on pain-selective spinal neurons (iv). Activated MOR1 induces central mechanisms of analgesia (v).