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 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.

Bile Acid Signaling in Metabolic Disease and Drug Therapy

“…TGR5 is expressed in astrocytes and neurons, and is activated by neurosteroids, and functions as a neurosteroid receptor (Keitel et al, 2010). Another study showed that TGR5 may mediate bile acid-induced itch and analgesia associated with cholestasis (Alemi et al, 2013a). In this study, the investigators identified TGR5 in peptidergic neurons that transmit itch and pain in mouse dorsal root ganglia and in the spinal cord as well as in dermal macrophagecontaining opioids.…”

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

“…TGR5 has a wide tissue distribution, being most heavily expressed in the enteric nervous system ( 65 ); it is also present in spinal cord neurons ( 66 ) and the primary cilia of cholangiocytes ( 67 ). The consequences of this activation include release of the hormone glucagon-like peptide 1 (GLP-1), which has appetite-suppressing and antidiabetic effects ( 68 ).…”

The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

“…Bile acids are markedly increased in the circulation and tissues of patients with cholestatic liver disease and may contribute to the chronic and intractable pruritus that is a common feature of this condition (Hayashi and Majima, 1999). TGR5 is expressed in peptidergic small diameter primary sensory neurons innervating the skin, and activation by bile acids causes a TGR5-dependent hyperexcitability and stimulates the secretion of the itch-selective transmitter gastrin releasing peptide (Alemi et al, 2013). The intradermal injection of bile acids and TGR5-selective agonists also caused robust scratching in wild-type but not tgr5 2/2 mice, whereas gainof-function transgenic mice exhibit a spontaneous pruritus.…”