The TGR5 receptor mediates bile acid-induced itch and analgesia

被引:305
|
作者
Alemi, Farzad [1 ]
Kwon, Edwin [1 ]
Poole, Daniel P. [2 ]
Lieu, TinaMarie [3 ]
Lyo, Victoria [1 ]
Cattaruzza, Fiore [1 ]
Cevikbas, Ferda [4 ]
Steinhoff, Martin [4 ]
Nassini, Romina [5 ]
Materazzi, Serena [5 ]
Guerrero-Alba, Raquel [6 ]
Valdez-Morales, Eduardo [6 ]
Cottrell, Graeme S. [7 ]
Schoonjans, Kristina [8 ]
Geppetti, Pierangelo [5 ]
Vanner, Stephen J. [6 ]
Bunnett, Nigel W. [3 ]
Corvera, Carlos U. [1 ]
机构
[1] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94121 USA
[2] Univ Melbourne, Dept Anat & Neurosci, Parkville, Vic 3052, Australia
[3] Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia
[4] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94121 USA
[5] Univ Florence, Dept Preclin & Clin Pharmacol, Florence, Italy
[6] Queens Univ, Gastrointestinal Dis Res Unit, Div Gastroenterol, Kingston, ON, Canada
[7] Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England
[8] Sch Life Sci, Inst Bioengn, Lab Integrat & Syst Physiol, Lausanne, Switzerland
来源
JOURNAL OF CLINICAL INVESTIGATION | 2013年 / 123卷 / 04期
基金
澳大利亚国家健康与医学研究理事会; 瑞士国家科学基金会;
关键词
GENE-RELATED PEPTIDE; SUBSTANCE-P; SYNAPTIC-TRANSMISSION; INTRATHECAL MORPHINE; CEREBROSPINAL-FLUID; LEUCINE-ENKEPHALIN; SENSORY NEURONS; GPBAR1; TGR5; SPINAL-CORD; RAT MODEL;
D O I
10.1172/JCI64551
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:1513 / 1530
页数:18
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