Alpha-lipoic Acid suppresses P2X receptor activities and visceral hypersensitivity to colorectal distention in diabetic rats

Ji Hu,Yu Feng,Xin Qin,Pan-Pan Yang,Zhen-Yuan Song,Qian Sun,Guang-Yin Xu,Hong-Hong Zhang

doi:10.1038/s41598-017-04283-7

Abstract

The present study was designed to investigate the roles of P2X3 receptors in dorsal root ganglion (DRG) neurons in colonic hypersensitivity and the effects of alpha-lipoic acid (ALA) on P2X3 receptor activity and colonic hypersensitivity of diabetic rats. Streptozotocin (STZ) was used to induce diabetic model. Abdominal withdrawal reflex (AWR) responding to colorectal distention (CRD) was recorded as colonic sensitivity. ATP-induced current density of colon-specific DRG (T13-L2 DRGs) neurons was measured with whole-cell patch clamp. The expression of P2X3Rs of T13-L2 DRGs was measured by western blot analysis. The results showed that AWR scores significantly increased after STZ injection. P2X3R expression and ATP current density of T13-L2 DRG neurons were enhanced in diabetic rats. Intraperitoneal injection with ALA once a day for 1 week remarkably reduced P2X3R expression and ATP current density in diabetic rats. Importantly, ALA treatment attenuated colonic hypersensitivity in diabetic rats. Our data suggest that STZ injection increases expression and function of P2X3 receptors of colon-specific DRG neurons, thus contributing to colonic hypersensitivity in diabetic rats. Administration of ALA attenuates diabetic colonic hypersensitivity, which is most likely mediated by suppressing expression and function of P2X3 receptors in DRGs of diabetic rats.

Highlights

Gastrointestinal dysfunction is one of the chronic complications of diabetes mellitus
We examined the expression of P2X3 receptors and recorded ATP induced-currents in the colon-specific projecting dorsal root ganglia (DRG) neurons from control and STZ-induced diabetic rats
The Abdominal withdrawal reflex (AWR) was increased in 40 mmHg colorectal distention pressure at 2 weeks after STZ injection (Fig. 1A, n = 10 for each group, *p < 0.05, compared with CON, Friedman ANOVA)

Summary

Introduction

Gastrointestinal dysfunction is one of the chronic complications of diabetes mellitus. Studies have shown that plasticity of voltage-gated ion channels on primary sensory neurons was involved in visceral hypersensitivity induced by diabetes. Our previous study found that changes in Nav1.7 and Nav1.8 expression and function resulted in increased excitability of the colon-specific DRG neurons and diabetic colonic hypersensitivity. Our previous studies found that the expression and function of P2X3 receptors were increased in rats with diabetic neuropathic pain. We examined the expression of P2X3 receptors and recorded ATP induced-currents in the colon-specific projecting DRG neurons from control and STZ-induced diabetic rats. Our data demonstrated for the first time, to the best of our knowledge, that STZ-induced diabetes increased the expression and function of P2X3 receptors in the colon-specific DRG neurons. ALA treatment suppressed P2X3 receptor expression, and reduced channel current density

Methods

Results

Conclusion