Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/117594
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Type: Journal article
Title: Tetrodotoxin-sensitive voltage-gated sodium channels regulate bladder afferent responses to distension
Author: Grundy, L.
Erickson, A.
Caldwell, A.
Garcia-Caraballo, S.
Rychkov, G.
Harrington, A.
Brierley, S.
Citation: Pain, 2018; 159(12):2573-2584
Publisher: Lippincott Williams & Wilkins
Issue Date: 2018
ISSN: 0304-3959
1872-6623
Statement of
Responsibility: 
Luke Grundy, Andelain Erickson, Ashlee Caldwell, Sonia Garcia-Caraballo, Grigori Rychkov, Andrea Harrington, Stuart M. Brierley
Abstract: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a prevalent, chronic bladder disorder that negatively impacts the quality of life for ∼5% of the western population. Hypersensitivity of mechanosensory afferents embedded within the bladder wall is considered a key component in mediating IC/BPS symptoms. Bladder infusion of voltage-gated sodium (Nav) channel blockers show clinical efficacy in treating IC/BPS symptoms; however, the current repertoire of Nav channels expressed by and contributing to bladder afferent function is unknown. We used single-cell reverse-transcription polymerase chain reaction of retrogradely traced bladder-innervating dorsal root ganglia (DRG) neurons to determine the expression profile of Nav channels, and patch-clamp recordings to characterise the contribution of tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Nav channels to total sodium current and neuronal excitability. We determined the TTX-S and TTX-R contribution to mechanosensitive bladder afferent responses ex vivo and spinal dorsal horn activation in vivo. Single-cell reverse-transcription polymerase chain reaction of bladder-innervating DRG neurons revealed significant heterogeneity in Nav channel coexpression patterns. However, TTX-S Nav channels contribute the vast majority of the total sodium current density and regulate the neuronal excitability of bladder DRG neurons. Furthermore, TTX-S Nav channels mediate almost all bladder afferent responses to distension. In vivo intrabladder infusion of TTX significantly reduces activation of dorsal horn neurons within the spinal cord to bladder distension. These data provide the first comprehensive analysis of Nav channel expression within sensory afferents innervating the bladder. They also demonstrate an essential role for TTX-S Nav channel regulation of bladder-innervating DRG neuroexcitability, bladder afferent responses to distension, and nociceptive signalling to the spinal cord.
Keywords: Bladder; afferent; spinal cord; nociception; DRG; Nav; TTX
Rights: © 2018 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
DOI: 10.1097/j.pain.0000000000001368
Grant ID: http://purl.org/au-research/grants/nhmrc/1126378
http://purl.org/au-research/grants/nhmrc/1083480
http://purl.org/au-research/grants/nhmrc/1139366
http://purl.org/au-research/grants/nhmrc/1140297
http://purl.org/au-research/grants/arc/DE130100223
http://purl.org/au-research/grants/arc/DP180101395
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