Bile acids reach out to the spinal cord: new insights to the pathogenesis of itch and analgesia in cholestatic liver disease

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.

Fig 1

Model for the pathogenesis of cholestatic liver disease-associated itch and altered analgesia. Cholestasis results in increased levels of circulating bile acids, autotaxin, and other potential pruritogens. Bile acids in skin may signal through their receptor TGR5 on peripheral sensory nerves to stimulate release of Gastrin-releasing peptide (GRP) and opioids by spinal neurons in the dorsal horn of the spinal cord. These neurotransmitters activate specific spinal neurons to induce itch. Autotaxin catalyzes the production of lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC), which can stimulate release of histamine or act directly on sensory nerves to induce itch. Bile acids could mediate analgesia by several mechanisms. In the skin, bile acids could activate TGR5 expressed on dermal macrophage to stimulate release of opioids. Bile acids may also activate TGR5 expressed on spinal neurons to stimulate release of opioids. BA, bile acids; DRG, dorsal root ganglion; LPA, lysophosphatidic acid; LPC, lysophosphatidylcholine.