Abstract
Chronic visceral pain in patients with irritable bowel syndrome (IBS) has been difficult to treat effectively partially because its pathophysiology is not fully understood. Recent studies show that norepinephrine (NE) plays an important role in the development of visceral hypersensitivity. In this study, we designed to investigate the role of adrenergic signaling in visceral hypersensitivity induced by heterotypical intermittent stress (HIS). Abdominal withdrawal reflex scores (AWRs) used as visceral sensitivity were determined by measuring the visceromoter responses to colorectal distension. Colon-specific dorsal root ganglia neurons (DRGs) were labeled by injection of DiI into the colon wall and were acutely dissociated for whole-cell patch-clamp recordings. Blood plasma level of NE was measured using radioimmunoassay kits. The expression of β2-adrenoceptors was measured by western blotting. We showed that HIS-induced visceral hypersensitivity was attenuated by systemic administration of a β-adrenoceptor antagonist propranolol, in a dose-dependent manner, but not by a α-adrenoceptor antagonist phentolamine. Using specific β–adrenoceptor antagonists, HIS-induced visceral hypersensitivity was alleviated by β2 adrenoceptor antagonist but not by β1- or β3-adrenoceptor antagonist. Administration of a selective β2-adrenoceptor antagonist also normalized hyperexcitability of colon-innervating DRG neurons of HIS rats. Furthermore, administration of β-adrenoceptor antagonist suppressed sustained potassium current density (I K) without any alteration of fast-inactivating potassium current density (I A). Conversely, administration of NE enhanced the neuronal excitability and produced visceral hypersensitivity in healthy control rats, and blocked by β2-adrenoceptor antagonists. In addition, HIS significantly enhanced the NE concentration in the blood plasma but did not change the expression of β2-adrenoceptor in DRGs and the muscularis externa of the colon. The present study might provide a potential molecular target for therapy of visceral hypersensitivity in patents with IBS.
Highlights
Irritable bowel syndrome (IBS), a common functional gastrointestinal disorder, is defined by recurrent symptoms of abdominal pain or discomfort associated with alterations in bowel habits [1]
Abdominal withdrawal reflex scores (AWRs) scores were significantly increased at distention pressures of 40 mmHg at 48 hours after heterotypical intermittent stress (HIS)
HIS induced visceral hypersensitivity to colorectal distention (CRD) lasted for 24 hours and returned to baseline by 48 hours in male SD rats after termination of the last stressor, which is consistent with our previous study [22]
Summary
Irritable bowel syndrome (IBS), a common functional gastrointestinal disorder, is defined by recurrent symptoms of abdominal pain or discomfort associated with alterations in bowel habits [1]. Clinical studies demonstrate that chronic stress plays an important role in the pathophysiology of IBS [2,3,4]. Alterations in adrenergic signaling have been implicated in the development of visceral hypersensitivity [5,6,7]. It is reported that chronic stress may induce abnormal expressions of brain G proteins, colonic alpha (2A)adrenoceptors, and norepinephrine (NE) reuptake transporter (NET), which may be responsible for the abnormalities of abdominal sensation in IBS [8]. Previous study showed that the blockade of a1/a2- and b1/b2-adernoreceptors before the daily application of chronic stress prevented the induction of visceral hypersensitivity in male Wistar rats [6]. Which subtype of the adrenergic receptors involves in the induction of visceral hypersensitivity following chronic stress remains unclear
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