Abstract
Although 5-HT has been implicated in cholestatic itch and antinociception, two common phenomena in patients with cholestatic disease, the roles of 5-HT receptor subtypes are unclear. Herein, we investigated the roles of 5-HT receptors in itch and antinociception associated with cholestasis, which was induced by common bile duct ligation (BDL) in rats. 5-HT-induced enhanced scratching and antinociception to mechanical and heat stimuli were demonstrated in BDL rats. 5-HT level in the skin and spinal cord was significantly increased in BDL rats. Quantitative RT-PCR analysis showed 5-HT1B, 5-HT1D, 5-HT2A, 5-HT3A, 5-HT5B, 5-HT6, and 5-HT7 were up-regulated in peripheral nervous system and 5-HT1A, 5-HT1F, 5-HT2B, and 5-HT3A were down-regulated in the spinal cord of BDL rats. Intradermal 5-HT2, 5-HT3, and 5-HT7 receptor agonists induced scratching in BDL rats, whereas 5-HT3 agonist did not induce scratching in sham rats. 5-HT1A, 5-HT2, 5-HT3, and 5-HT7 agonists or antagonists suppressed itch in BDL rats. 5-HT1A agonist attenuated, but 5-HT1A antagonist enhanced antinociception in BDL rats. 5-HT2 and 5-HT3 agonists or antagonists attenuated antinociception in BDL rats. Our data suggested peripheral and central 5-HT system dynamically participated in itch and antinociception under cholestasis condition and targeting 5-HT receptors may be an effective treatment for cholestatic itch.
Highlights
Itch is an unpleasant somatic sensation that elicits a desire to scratch[1]
The results demonstrated that mRNA expression of multiple 5-HT receptors, including 5-HT1B, 5-HT1D, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT3A, 5-HT5B, 5-HT6, and 5-HT7, were up-regulated in trigeminal ganglia (TG) from bile duct ligation (BDL) rats compared to sham rats (Fig. 5B)
We further showed that the 5-HT level in the skin and spinal cord significantly increased, possible due to the increased 5-HT synthesis, in BDL rats compared to sham rats
Summary
Itch (pruritus) is an unpleasant somatic sensation that elicits a desire to scratch[1]. Serum concentrations of lysophosphatidic acid (LPA) and autotoxin (the enzyme that forms LPA) were significantly increased in cholestatic patients with pruritus and could directly activate dorsal root ganglia (DRG) neurons reflected by increased intracellular calcium[22], suggesting LPA is a potential mediator of cholestatic pruritus Bile acids, such as deoxycholic acid (DCA) and taurolithocholic acid (TLCA), bind to TGR5 ( known as GPR131 or GPBAR1) and activate transient receptor potential cation channel A1 (TRPA1) in primary sensory neurons and subsequently stimulates the release of itch-related neuropeptides, such as gastrin-releasing peptide (GRP) and natriuritic precursor peptide B (NPPB), in the spinal cord to transmit itch in mice[17,23]. We employed several pharmacological 5-HT receptors agonists and antagonists to elucidate the distinct roles of 5-HT receptors subtypes, especially 5-HT1A, 5-HT2, 5-HT3 and 5-HT7, in the modulation of itch and antinociception in BDL rats
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
