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Dexmedetomidine inhibits Tetrodotoxin-resistant Na(v)1.8 sodium channel activity through G(i/o)-dependent pathway in rat dorsal root ganglion neurons

BACKGROUND: Systemically administered dexmedetomidine (DEX), a selective α2 adrenergic receptor (α2-AR) agonists, produces analgesia and sedation. Peripherally restricted α2-AR antagonist could block the analgesic effect of systemic DEX on neuropathic pain, with no effect on sedation, indicating per...

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Autores principales: Gu, Xi-Yao, Liu, Ben-Long, Zang, Kai-Kai, Yang, Liu, Xu, Hua, Pan, Hai-Li, Zhao, Zhi-Qi, Zhang, Yu-Qiu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350947/
https://www.ncbi.nlm.nih.gov/pubmed/25761941
http://dx.doi.org/10.1186/s13041-015-0105-2
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author Gu, Xi-Yao
Liu, Ben-Long
Zang, Kai-Kai
Yang, Liu
Xu, Hua
Pan, Hai-Li
Zhao, Zhi-Qi
Zhang, Yu-Qiu
author_facet Gu, Xi-Yao
Liu, Ben-Long
Zang, Kai-Kai
Yang, Liu
Xu, Hua
Pan, Hai-Li
Zhao, Zhi-Qi
Zhang, Yu-Qiu
author_sort Gu, Xi-Yao
collection PubMed
description BACKGROUND: Systemically administered dexmedetomidine (DEX), a selective α2 adrenergic receptor (α2-AR) agonists, produces analgesia and sedation. Peripherally restricted α2-AR antagonist could block the analgesic effect of systemic DEX on neuropathic pain, with no effect on sedation, indicating peripheral analgesic effect of DEX. Tetrodotoxin-resistant (TTX-R) sodium channel Na(v)1.8 play important roles in the conduction of nociceptive sensation. Both α2-AR and Nav1.8 are found in small nociceptive DRG neurons. We, therefore, investigated the effects of DEX on the Na(v)1.8 currents in acutely dissociated small-diameter DRG neurons. RESULTS: Whole-cell patch-clamp recordings demonstrated that DEX concentration-dependently suppressed TTX-R Na(v)1.8 currents in small-diameter lumbar DRG neurons. DEX also shifted the steady-state inactivation curves of Na(v)1.8 in a hyperpolarizing direction and increased the threshold of action potential and decrease electrical and chemical stimuli-evoked firings in small-diameter DRG neurons. The α2-AR antagonist yohimbine or α2(A)-AR antagonist BRL44408 but not α2(B)-AR antagonist imiloxan blocked the inhibition of Na(v)1.8 currents by DEX. Immunohistochemistry results showed that Na(v)1.8 was predominantly expressed in peripherin-positive small-diameter DRG neurons, and some of them were α2(A)-AR-positive ones. Our electrophysiological recordings also demonstrated that DEX-induced inhibition of Na(v)1.8 currents was prevented by intracellular application of G-protein inhibitor GDPβ-s or G(i/o) proteins inhibitor pertussis toxin (PTX), and bath application of adenylate cyclase (AC) activator forskolin or membrane-permeable cAMP analogue 8-Bromo-cAMP (8-Br-cAMP). PKA inhibitor Rp-cAMP could mimic DEX-induced inhibition of Na(v)1.8 currents. CONCLUSIONS: We established a functional link between α2-AR and Na(v)1.8 in primary sensory neurons utilizing the G(i/o)/AC/cAMP/PKA pathway, which probably mediating peripheral analgesia of DEX.
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spelling pubmed-43509472015-03-06 Dexmedetomidine inhibits Tetrodotoxin-resistant Na(v)1.8 sodium channel activity through G(i/o)-dependent pathway in rat dorsal root ganglion neurons Gu, Xi-Yao Liu, Ben-Long Zang, Kai-Kai Yang, Liu Xu, Hua Pan, Hai-Li Zhao, Zhi-Qi Zhang, Yu-Qiu Mol Brain Research BACKGROUND: Systemically administered dexmedetomidine (DEX), a selective α2 adrenergic receptor (α2-AR) agonists, produces analgesia and sedation. Peripherally restricted α2-AR antagonist could block the analgesic effect of systemic DEX on neuropathic pain, with no effect on sedation, indicating peripheral analgesic effect of DEX. Tetrodotoxin-resistant (TTX-R) sodium channel Na(v)1.8 play important roles in the conduction of nociceptive sensation. Both α2-AR and Nav1.8 are found in small nociceptive DRG neurons. We, therefore, investigated the effects of DEX on the Na(v)1.8 currents in acutely dissociated small-diameter DRG neurons. RESULTS: Whole-cell patch-clamp recordings demonstrated that DEX concentration-dependently suppressed TTX-R Na(v)1.8 currents in small-diameter lumbar DRG neurons. DEX also shifted the steady-state inactivation curves of Na(v)1.8 in a hyperpolarizing direction and increased the threshold of action potential and decrease electrical and chemical stimuli-evoked firings in small-diameter DRG neurons. The α2-AR antagonist yohimbine or α2(A)-AR antagonist BRL44408 but not α2(B)-AR antagonist imiloxan blocked the inhibition of Na(v)1.8 currents by DEX. Immunohistochemistry results showed that Na(v)1.8 was predominantly expressed in peripherin-positive small-diameter DRG neurons, and some of them were α2(A)-AR-positive ones. Our electrophysiological recordings also demonstrated that DEX-induced inhibition of Na(v)1.8 currents was prevented by intracellular application of G-protein inhibitor GDPβ-s or G(i/o) proteins inhibitor pertussis toxin (PTX), and bath application of adenylate cyclase (AC) activator forskolin or membrane-permeable cAMP analogue 8-Bromo-cAMP (8-Br-cAMP). PKA inhibitor Rp-cAMP could mimic DEX-induced inhibition of Na(v)1.8 currents. CONCLUSIONS: We established a functional link between α2-AR and Na(v)1.8 in primary sensory neurons utilizing the G(i/o)/AC/cAMP/PKA pathway, which probably mediating peripheral analgesia of DEX. BioMed Central 2015-03-03 /pmc/articles/PMC4350947/ /pubmed/25761941 http://dx.doi.org/10.1186/s13041-015-0105-2 Text en © Gu et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Gu, Xi-Yao
Liu, Ben-Long
Zang, Kai-Kai
Yang, Liu
Xu, Hua
Pan, Hai-Li
Zhao, Zhi-Qi
Zhang, Yu-Qiu
Dexmedetomidine inhibits Tetrodotoxin-resistant Na(v)1.8 sodium channel activity through G(i/o)-dependent pathway in rat dorsal root ganglion neurons
title Dexmedetomidine inhibits Tetrodotoxin-resistant Na(v)1.8 sodium channel activity through G(i/o)-dependent pathway in rat dorsal root ganglion neurons
title_full Dexmedetomidine inhibits Tetrodotoxin-resistant Na(v)1.8 sodium channel activity through G(i/o)-dependent pathway in rat dorsal root ganglion neurons
title_fullStr Dexmedetomidine inhibits Tetrodotoxin-resistant Na(v)1.8 sodium channel activity through G(i/o)-dependent pathway in rat dorsal root ganglion neurons
title_full_unstemmed Dexmedetomidine inhibits Tetrodotoxin-resistant Na(v)1.8 sodium channel activity through G(i/o)-dependent pathway in rat dorsal root ganglion neurons
title_short Dexmedetomidine inhibits Tetrodotoxin-resistant Na(v)1.8 sodium channel activity through G(i/o)-dependent pathway in rat dorsal root ganglion neurons
title_sort dexmedetomidine inhibits tetrodotoxin-resistant na(v)1.8 sodium channel activity through g(i/o)-dependent pathway in rat dorsal root ganglion neurons
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350947/
https://www.ncbi.nlm.nih.gov/pubmed/25761941
http://dx.doi.org/10.1186/s13041-015-0105-2
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