Neonatal Colonic Inflammation Increases Spinal Transmission and Cystathionine β-Synthetase Expression in Spinal Dorsal Horn of Rats with Visceral Hypersensitivity.

Liting Zhao,Guang-Yin Xu,Rui-Xia Weng,Ping-An Zhang,Shan P Yu,Chuang-Ying Hu,Ying Xiao,Xuelian Liu

doi:10.3389/fphar.2017.00696

Abstract

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by chronic abdominal pain and alteration of bowel movements. The pathogenesis of visceral hypersensitivity in IBS patients remains largely unknown. Hydrogen sulfide (H2S) is reported to play an important role in development of visceral hyperalgesia. However, the role of H2S at spinal dorsal horn level remains elusive in visceral hypersensitivity. The aim of this study is designed to investigate how H2S takes part in visceral hypersensitivity of adult rats with neonatal colonic inflammation (NCI). Visceral hypersensitivity was induced by neonatal colonic injection of diluted acetic acid. Expression of an endogenous H2S synthesizing enzyme cystathionine β-synthetase (CBS) was determined by Western blot. Excitability and synaptic transmission of neurons in the substantia gelatinosa (SG) of spinal cord was recorded by patch clamping. Here, we showed that expression of CBS in the spinal dorsal horn was significantly upregulated in NCI rats. The frequency of glutamatergic synaptic activities in SG was markedly enhanced in NCI rats when compared with control rats. Application of NaHS increased the frequency of both spontaneous and miniature excitatory post-synaptic currents of SG neurons in control rats through a presynaptic mechanism. In contrast, application of AOAA, an inhibitor of CBS, dramatically suppressed the frequency of glutamatergic synaptic activities of SG neurons of NCI rats. Importantly, intrathecal injection of AOAA remarkably attenuated visceral hypersensitivity of NCI rats. These results suggest that H2S modulates pain signaling likely through a presynaptic mechanism in SG of spinal dorsal horn, thus providing a potential therapeutic strategy for treatment for chronic visceral pain in patients with IBS.

Highlights

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder affecting approximately 20% of populations worldwide (Sandler et al, 1984; Drossman et al, 2002)
CVH was determined by measuring AWR scores in response to colorectal distention (CRD) at age of 6 week for control (CON, n = 8) and neonatal colonic inflammation (NCI) (n = 8) rats
The conclusion is based on the following observations: (1) NCI leads to a significant increase in expression of CBS in spinal cord (SC) where receives input from T13-L2 dorsal root ganglion (DRG) neurons (Figure 1B); (2) NCI significantly increases neuronal excitability and excitatory synaptic transmission in substantia gelatinosa (SG) of spinal dorsal horn (Figures 2, 3); (3) Intrathecal injection of AOAA reversed the visceral hyperalgesia of rats with NCI and decreased excitatory synaptic transmission in SG (Figure 6); (4) Intrathecal injection of NaHS (2.5 μM) led to visceral pain and significantly increases excitatory synaptic transmission of SG in control rats (Figures 4, 5)

Summary

Introduction

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder affecting approximately 20% of populations worldwide (Sandler et al, 1984; Drossman et al, 2002). It is proved that the up-regulated expression of CBS and increase in excitation of DRG neurons caused visceral hyperalgesia in adult rats with heterotypic intermittent stress (Wang et al, 2012) as well as hyperalgesia in other animal models, such as neonatal maternal deprivation (Li et al, 2012) and diabetes (Zhang et al, 2013). The role of H2S at low concentration in SC is pro-nociceptive in LPS-induced mechanical inflammatory hypernociception (Cunha et al, 2008). It is not clear how the H2S in the SC is involved in the regulation of visceral pain

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