Small-Conductance Ca2+-Activated K+ Channel 2 in the Dorsal Horn of Spinal Cord Participates in Visceral Hypersensitivity in Rats.

Yu Song,Yong-Mei Zhang,Jun-Sheng Zhu,Lei Du,Gongliang Zhang,Rong Hua,Robert W. Stackman,Si-Ting Huang

doi:10.3389/fphar.2018.00840

Abstract

Visceral hypersensitivity is a highly complex and subjective phenomenon associated with multiple levels of the nervous system and a wide range of neurotransmission. The dorsal horn (DH) in spinal cord relays the peripheral sensory information into the brain. Small conductance Ca2+-activated K+ (SK) channels regulate neuronal excitability and firing by allowing K+ to efflux in response to increase in the intracellular Ca2+ level. In this study, we examined the influence of SK2 channels in the spinal DH on the pathogenesis of visceral hypersensitivity induced by colorectal distension (CRD) in rats. Electrophysiological results showed that rats with visceral hypersensitivity presented a decrease in the SK channel-mediated afterhyperpolarization current (IAHP), and an increase in neuronal firing rates and c-Fos positive staining in the spinal DH. Western blot data revealed a decrease in the SK2 channel protein in the membrane fraction. Moreover, intrathecal administration of the SK2 channel activator 1-EBIO or CyPPA alleviated visceral hypersensitivity, reversed the decrease in IAHP and the increase in neuronal firing rates in spinal DH in rats that experienced CRD. 1-EBIO or CyPPA effect could be prevented by SK2 channel blocker apamin. CRD induced an increase in c-Fos protein expression in the spinal DH, which was prevented by 1-EBIO. Together, these data suggest that visceral hypersensitivity and pain is associated with a decrease in the number and function of membrane SK2 channels in the spinal DH. Pharmacological manipulation of SK2 channels may open a new avenue for the treatment of visceral hypersensitivity and pain.Highlights: -Neonatal colorectal distension induced visceral hypersensitivity in rats.-Visceral hypersensitivity rats presented a decrease in afterhyperpolarization current (IAHP) and membrane SK2 channel protein in the spinal dorsal horn.-Visceral hypersensitivity rats presented an increase in neuronal firing rate in the spinal dorsal horn.-Intrathecal administration of SK2 channel activator 1-EBIO or CyPPA prevented visceral hypersensitivity and decrease in IAHP.

Highlights

Visceral hypersensitivity is a hallmark of irritable bowel syndrome and other gastrointestinal disorders that cause pain
We explored the role of spinal SK2 channels in visceral hypersensitivity in a rat model developed by colorectal distension (CRD)
Rats with visceral hypersensitivity presented a significant decrease in membrane SK2 channel protein and in the SK channel-mediated afterhyperpolarization current (IAHP), and an increase in neuronal firing rate in the spinal dorsal horn (DH)

Summary

Introduction

Visceral hypersensitivity is a hallmark of irritable bowel syndrome and other gastrointestinal disorders that cause pain. The dorsal horn (DH) in spinal cord is a major component of the nociceptive system, and the alteration in spinal neuronal activity may modulate visceral hypersensitivity and pain (Kawamata and Omote, 1996; Wang et al, 2014; Fu et al, 2016; Medrano et al, 2016). Visceral hypersensitivity can be induced by the sensitization of primary sensory neurons innervating the visceral organs, hyperexcitability of spinal ascending neurons receiving visceral afferents, and/or dysregulation of descending pathways that modulate spinal nociceptive transmission (Sengupta, 2009). Previous studies revealed that nociceptive neurons in the spinal DH presented higher excitability and exaggerated sensory reflex to the visceral stimuli in subjects with visceral hypersensitivity (Lu et al, 2007; Hipolito et al, 2015; Wu et al, 2016). Neuronal excitability is modulated by membrane ion channels, for example, small conductance Ca2+-activated K+ (SK) channels (Adelman et al, 2012)

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