Adrenergic β2-receptors Mediates Visceral Hypersensitivity Induced By Heterotypic Intermittent Stress In Rats

Chronic visceral pain in patients with irritable bowel syndrome (IBS) has beendifficult to treat effectively partially because its pathophysiology is not fully understood.Recent studies show that norepinephrine (NE) plays an important role in thedevelopment of visceral hypersensitivity. In this study, we designed to investigate therole of adrenergic signaling in visceral hypersensitivity induced by heterotypicalintermittent stress (HIS). Abdominal withdrawal reflex scores (AWRs) used as visceralsensitivity were determined by measuring the visceromoter responses to colorectaldistension. Colon-specific dorsal root ganglia (DRG) neurons were labeled by injectionof DiI into the colon wall and were acutely dissociated for whole-cell patch-clamprecordings. Blood plasma level of NE was measured using enzyme-linkedimmunosorbent kits. The expression of β2-adrenoceptors was measured by westernblotting. We showed that HIS-induced visceral hypersensitivity was attenuated bysystemic administration of a β-adrenoceptor antagonist propranolol, in a dose-dependentmanner, but not by an α-adrenoceptor antagonist phentolamine. Using specificβ–adrenoceptor antagonists, HIS-induced visceral hypersensitivity was alleviated by β2adrenoceptor antagonist but not by β1-or β3-adrenoceptor antagonist. Administration ofa selective β2-adrenoceptor antagonist also normalized hyperexcitability ofcolon-innervating DRG neurons of HIS rats. Furthermore, administration of aβ-adrenoceptor antagonist suppressed sustained potassium current density (IK) withoutany alteration of fast-inactivating potassium current density (IA). Conversely,administration of NE enhanced the neuronal excitability and produced visceral hypersensitivity in healthy control rats, and blocked by β2-adrenoceptor antagonists. Inaddition, HIS significantly enhanced the NE concentration in the blood plasma but didnot alter the expression of β2-adrenoceptor in DRGs and the muscularis externa of thecolon. The present study might provide a potential molecular target for therapy ofvisceral hypersensitivity in patents with IBS.