Small-Conductance Ca2+-Activated K+ Channels 2 in the Hypothalamic Paraventricular Nucleus Precipitates Visceral Hypersensitivity Induced by Neonatal Colorectal Distension in Rats.

Yong-Mei Zhang,Rong Hua,Ning-Ning Ji,Ke Wu,Lei Du,Ying Wang,Zi-Yang Chen

doi:10.3389/fphar.2020.605618

Abstract

Visceral hypersensitivity is one of the pivotal pathophysiological features of visceral pain in irritable bowel syndrome (IBS). Small-conductance Ca2+-activated K+ channel (SK) is critical for a variety of functions in the central nervous system (CNS), nonetheless, whether it is involved in the pathogenesis of visceral hypersensitivity remain elusive. In this study, we examined mechanism of SK2 in hypothalamic paraventricular nucleus (PVN) in the pathogenesis of visceral hypersensitivity induced by neonatal colorectal distension (CRD). Rats undergoing neonatal CRD presented with visceral hypersensitivity as well as downregulated membrane SK2 channel and p-PKA. Intra-PVN administration of either the membrane protein transport inhibitor dynasore or the SK2 activator 1-EBIO upregulated the expression of membrane SK2 in PVN and mitigated visceral hypersensitivity. In addition, 1-EBIO administration reversed the increase in neuronal firing rates in PVN in rats undergoing neonatal CRD. On the contrary, intra-PVN administration of either the SK2 inhibitor apamin or PKA activator 8-Br-cAMP exacerbated the visceral hypersensitivity. Taken together, these findings demonstrated that visceral hypersensitivity is related to the downregulation of membrane SK2 in PVN, which may be attributed to the activation of PKA; pharmacologic activation of SK2 alleviated visceral hypersensitivity, which brings prospect of SK2 activators as a new intervention for visceral pain.

Highlights

Visceral hypersensitivity is one of the key pathophysiological features of irritable bowel syndrome (IBS) as well as other conditions with visceral pain (Chey et al, 2015)
Western blotting data revealed that the expression of paraventricular nucleus (PVN) SK2 channel protein in membrane fraction was decreased in rats subjected to neonatal colorectal distension (CRD) (Figure 2A)
These findings suggested that neonatal CRD contributed to the internalization of SK2 channels

Summary

Introduction

Visceral hypersensitivity is one of the key pathophysiological features of irritable bowel syndrome (IBS) as well as other conditions with visceral pain (Chey et al, 2015). Our prior studies confirmed that CRD induced visceral hypersensitivity as well as enhanced excitability of CRF neurons, with both CRF protein expression in PVN and plasma cortisol levels increased (Yu et al, 2014; Chen et al, 2015). The activation of CRF neurons in PVN leads to the CRF release, resulting in the undermined analgesia (Lariviere and Melzack, 2000) and exacerbated neuropathic pain (Fu et al, 2016), thereby implying the pivotal role of CRF neurons in PVN in modulating visceral hypersensitivity. The mechanism underpinning the elevated excitability of CRF neurons in PVN in the pathogenesis of visceral hypersensitivity remains elusive

Methods

Results

Conclusion