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Article: Suppression of Pax2 Attenuates Allodynia and Hyperalgesia through ET-1–ETAR–NFAT5 Signaling in a Rat Model of Neuropathic Pain

TitleSuppression of Pax2 Attenuates Allodynia and Hyperalgesia through ET-1–ETAR–NFAT5 Signaling in a Rat Model of Neuropathic Pain
Authors
Keywordsneuropathic
Endothelin-1
endothelin type A receptor
painpaired box gene 2
nuclear factor of activated T-cells 5
nuclear factor-kappa B
Issue Date2018
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/neuroscience
Citation
Neuroscience, 2018, v. 384, p. 139-151 How to Cite?
AbstractEndothelin-1 (ET-1) and its receptors (ETAR/ETBR) emerge to be a key signaling axis in neuropathic pain processing and are recognized as new therapeutic targets. Yet, little is known on the functional regulation of ET-1 axis during neuropathic pain. Bioinformatics analysis indicated that paired box gene 2 (Pax2) or nuclear factor of activated T-cells 5 (NFAT5), two transcription factors involved in the modulation of neurotransmission, may regulate ET-1. Therefore, we hypothesized that ET-1 axis may be regulated by Pax2 or NFAT5 in the development of neuropathic pain. After partial sciatic nerve ligation (pSNL), rats displayed allodynia and hyperalgesia, which was associated with increased mRNA and protein expressions of spinal Pax2, NFAT5, and mRNA levels of ET-1 and ETAR, but not ETBR. Knockdown of Pax2 or NFAT5 with siRNA, or inhibition of ETAR with BQ-123 attenuated pSNL-induced pain-like behaviors. At molecular level, Pax2 siRNA, but not NFAT5 siRNA, downregulated ET-1 and ETAR, while ETAR inhibitor reduced NFAT5, indicating Pax2 in the upstream of ET-1 axis with NFAT5 in the downstream. Further, suppression of Pax2 (inhibiting ET-1) or impairment of ET-1 signaling (inhibition of ETAR and/or decrease of NFAT5) deactivated mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, supporting the significance of functional regulation of ET-1 axis in neuropathic pain signaling. These findings demonstrate that Pax2 targeting ET-1–ETAR–NFAT5 is a novel regulatory mechanism underlying neuropathic pain.
Persistent Identifierhttp://hdl.handle.net/10722/262586
ISSN
2023 Impact Factor: 2.9
2023 SCImago Journal Rankings: 0.903
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorTai, WL-
dc.contributor.authorPan, Z-
dc.contributor.authorSun, L-
dc.contributor.authorLi, H-
dc.contributor.authorGu, P-
dc.contributor.authorWong, SCS-
dc.contributor.authorChung, SK-
dc.contributor.authorCheung, CW-
dc.date.accessioned2018-10-04T02:47:03Z-
dc.date.available2018-10-04T02:47:03Z-
dc.date.issued2018-
dc.identifier.citationNeuroscience, 2018, v. 384, p. 139-151-
dc.identifier.issn0306-4522-
dc.identifier.urihttp://hdl.handle.net/10722/262586-
dc.description.abstractEndothelin-1 (ET-1) and its receptors (ETAR/ETBR) emerge to be a key signaling axis in neuropathic pain processing and are recognized as new therapeutic targets. Yet, little is known on the functional regulation of ET-1 axis during neuropathic pain. Bioinformatics analysis indicated that paired box gene 2 (Pax2) or nuclear factor of activated T-cells 5 (NFAT5), two transcription factors involved in the modulation of neurotransmission, may regulate ET-1. Therefore, we hypothesized that ET-1 axis may be regulated by Pax2 or NFAT5 in the development of neuropathic pain. After partial sciatic nerve ligation (pSNL), rats displayed allodynia and hyperalgesia, which was associated with increased mRNA and protein expressions of spinal Pax2, NFAT5, and mRNA levels of ET-1 and ETAR, but not ETBR. Knockdown of Pax2 or NFAT5 with siRNA, or inhibition of ETAR with BQ-123 attenuated pSNL-induced pain-like behaviors. At molecular level, Pax2 siRNA, but not NFAT5 siRNA, downregulated ET-1 and ETAR, while ETAR inhibitor reduced NFAT5, indicating Pax2 in the upstream of ET-1 axis with NFAT5 in the downstream. Further, suppression of Pax2 (inhibiting ET-1) or impairment of ET-1 signaling (inhibition of ETAR and/or decrease of NFAT5) deactivated mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, supporting the significance of functional regulation of ET-1 axis in neuropathic pain signaling. These findings demonstrate that Pax2 targeting ET-1–ETAR–NFAT5 is a novel regulatory mechanism underlying neuropathic pain.-
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/neuroscience-
dc.relation.ispartofNeuroscience-
dc.subjectneuropathic-
dc.subjectEndothelin-1-
dc.subjectendothelin type A receptor-
dc.subjectpainpaired box gene 2-
dc.subjectnuclear factor of activated T-cells 5-
dc.subjectnuclear factor-kappa B-
dc.titleSuppression of Pax2 Attenuates Allodynia and Hyperalgesia through ET-1–ETAR–NFAT5 Signaling in a Rat Model of Neuropathic Pain-
dc.typeArticle-
dc.identifier.emailWong, SCS: wongstan@hku.hk-
dc.identifier.emailChung, SK: skchung@hkucc.hku.hk-
dc.identifier.emailCheung, CW: cheucw@hku.hk-
dc.identifier.authorityWong, SCS=rp01789-
dc.identifier.authorityChung, SK=rp00381-
dc.identifier.authorityCheung, CW=rp00244-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.neuroscience.2018.05.024-
dc.identifier.scopuseid_2-s2.0-85048166637-
dc.identifier.hkuros293716-
dc.identifier.hkuros294178-
dc.identifier.volume384-
dc.identifier.spage139-
dc.identifier.epage151-
dc.identifier.isiWOS:000436608600013-
dc.publisher.placeNetherlands-
dc.identifier.issnl0306-4522-

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