Activation of Neuronal Voltage-Gated Potassium Kv7/KCNQ/M-Current by a Novel Channel Opener SCR2682 for Alleviation of Chronic Pain.

Action Potentials Analgesics / pharmacology Animals Cells, Cultured Chronic Pain / drug therapy Ganglia, Spinal / drug effects KCNQ2 Potassium Channel / agonists Male Membrane Transport Modulators / pharmacology Pyridines / pharmacology Rats Rats, Sprague-Dawley

Journal

The Journal of pharmacology and experimental therapeutics
ISSN: 1521-0103
Titre abrégé: J Pharmacol Exp Ther
Pays: United States
ID NLM: 0376362

Informations de publication

Date de publication:
04 2021
Historique:
received: 29 09 2020
accepted: 06 01 2021
pubmed: 13 1 2021
medline: 15 5 2021
entrez: 12 1 2021
Statut: ppublish

Résumé

Treatment of chronic pain remains an unmet medical need. The neuronal voltage-gated potassium Kv7/KCNQ/M channel has been implicated as a therapeutic target for chronic pain. However, whether pharmacological activation of the Kv7 channel can alleviate pain remains elusive. In this study, we show that selective activation of native M-currents by a novel channel opener SCR2682 reduces repetitive firings of dorsal root ganglia (DRG) sensory neurons. Intraperitoneal administration of SCR2682 relieves mechanical allodynia and thermal hyperalgesia in rat models of pain induced by complete Freund's adjuvant (CFA) or spared nerve injury (SNI) in a dose-dependent manner without affecting locomotor activity. The antinociceptive efficacy of SCR2682 can be reversed by the channel-specific blocker XE991. Furthermore, SCR2682 increases Kv7.2/KCNQ2 mRNA and protein expression in DRG neurons from rats in the SNI model of neuropathic pain. Taken together, pharmacological activation of neuronal Kv7 channels by opener SCR2682 can alleviate pain in rats, thus possessing therapeutic potential for chronic pain or hyperexcitability-related neurologic disorders. SIGNIFICANCE STATEMENT: A novel voltage-gated potassium Kv7 channel opener SCR2682 inhibits action potential firings in dorsal root ganglia sensory neurons and exhibits efficacy in antinociception, thus possessing a developmental potential for treatment of chronic pain or epilepsy.

Identifiants

DOI: 10.1124/jpet.120.000357 PMID: 33431609
pubmed: 33431609
pii: jpet.120.000357
doi: 10.1124/jpet.120.000357
doi:

Substances chimiques

Analgesics 0
KCNQ2 Potassium Channel 0
Membrane Transport Modulators 0
Pyridines 0
SCR2682 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

20-28

Informations de copyright

Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.

Déclaration de conflit d'intérêts

No author has an actual or perceived conflict of interest with the contents of this article.

Auteurs

Jing Wang (J)

Department of Pharmacology, School of Pharmacy at Qingdao University Medical College, Qingdao, China (J.W., Y.L., F.H., J.Y., X.G., X.H., C.J., K.W.); Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, China (Y.L., K.W.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (Y.L., K.W.) jucx@qdu.edu.cn wangkw@qdu.edu.cn.

Yani Liu (Y)

Department of Pharmacology, School of Pharmacy at Qingdao University Medical College, Qingdao, China (J.W., Y.L., F.H., J.Y., X.G., X.H., C.J., K.W.); Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, China (Y.L., K.W.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (Y.L., K.W.).

Fang Hu (F)

Department of Pharmacology, School of Pharmacy at Qingdao University Medical College, Qingdao, China (J.W., Y.L., F.H., J.Y., X.G., X.H., C.J., K.W.); Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, China (Y.L., K.W.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (Y.L., K.W.).

Jiuyong Yang (J)

Department of Pharmacology, School of Pharmacy at Qingdao University Medical College, Qingdao, China (J.W., Y.L., F.H., J.Y., X.G., X.H., C.J., K.W.); Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, China (Y.L., K.W.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (Y.L., K.W.).

Xiaoyu Guo (X)

Department of Pharmacology, School of Pharmacy at Qingdao University Medical College, Qingdao, China (J.W., Y.L., F.H., J.Y., X.G., X.H., C.J., K.W.); Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, China (Y.L., K.W.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (Y.L., K.W.).

Xingming Hou (X)

Department of Pharmacology, School of Pharmacy at Qingdao University Medical College, Qingdao, China (J.W., Y.L., F.H., J.Y., X.G., X.H., C.J., K.W.); Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, China (Y.L., K.W.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (Y.L., K.W.).

Chuanxia Ju (C)

Department of Pharmacology, School of Pharmacy at Qingdao University Medical College, Qingdao, China (J.W., Y.L., F.H., J.Y., X.G., X.H., C.J., K.W.); Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, China (Y.L., K.W.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (Y.L., K.W.) jucx@qdu.edu.cn wangkw@qdu.edu.cn.

KeWei Wang (K)

Department of Pharmacology, School of Pharmacy at Qingdao University Medical College, Qingdao, China (J.W., Y.L., F.H., J.Y., X.G., X.H., C.J., K.W.); Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, China (Y.L., K.W.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (Y.L., K.W.) jucx@qdu.edu.cn wangkw@qdu.edu.cn.

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Classifications MeSH

questionsmedicales.fr › Phénomènes physiologiques de l'appareil locomoteur et du système nerveux › Phénomènes physiologiques du système nerveux › Potentiels de membrane › Potentiels d'action › Activation of Neuronal Voltage-Gated Potassium...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents du système nerveux central › Analgésiques › Activation of Neuronal Voltage-Gated Potassium...
questionsmedicales.fr › Eucaryotes › Animaux › Activation of Neuronal Voltage-Gated Potassium...
questionsmedicales.fr › Cellules › Cellules cultivées › Activation of Neuronal Voltage-Gated Potassium...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Manifestations neurologiques › Douleur chronique › Activation of Neuronal Voltage-Gated Potassium...
questionsmedicales.fr › Système nerveux › Système nerveux périphérique › Nerfs périphériques › Nerfs spinaux › Racines des nerfs spinaux › Ganglions sensitifs des nerfs spinaux › Activation of Neuronal Voltage-Gated Potassium...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Canaux ioniques › Canaux potassiques › Canaux potassiques voltage-dépendants › Canaux potassiques rectifiants retardés › Canaux potassiques KNCQ › Canal potassique KCNQ2 › Activation of Neuronal Voltage-Gated Potassium...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Modulateurs du transport transmembranaire › Activation of Neuronal Voltage-Gated Potassium...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyridines › Activation of Neuronal Voltage-Gated Potassium...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › Activation of Neuronal Voltage-Gated Potassium...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › Rat Sprague-Dawley › Activation of Neuronal Voltage-Gated Potassium...