Peripheral and spinal 5-HT receptors participate in cholestatic itch and antinociception induced by bile duct ligation in rats

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-HT_1B, 5-HT_1D, 5-HT_2A, 5-HT_3A, 5-HT_5B, 5-HT₆, and 5-HT₇ were up-regulated in peripheral nervous system and 5-HT_1A, 5-HT_1F, 5-HT_2B, and 5-HT_3A 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-HT_1A, 5-HT₂, 5-HT₃, and 5-HT₇ agonists or antagonists suppressed itch in BDL rats. 5-HT_1A agonist attenuated, but 5-HT_1A 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.