Reduced pain sensitivity of episodic pain syndrome model mice carrying a Nav1.9 mutation by ANP-230, a novel sodium channel blocker
The sodium channel Nav1.9 is expressed in the sensory neurons of small diameter dorsal root ganglia that transmit pain signals, and gain-of-function Nav1.9 mutations have been associated with both painful and painless disorders. We initially determined that some Nav1.9 mutations are responsible for...
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Elsevier
2023-04-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844023026300 |
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| author | Hiroko Okuda Sumiko Inoue Yoshihiro Oyamada Akio Koizumi Shohab Youssefian |
| author_facet | Hiroko Okuda Sumiko Inoue Yoshihiro Oyamada Akio Koizumi Shohab Youssefian |
| author_sort | Hiroko Okuda |
| collection | DOAJ |
| description | The sodium channel Nav1.9 is expressed in the sensory neurons of small diameter dorsal root ganglia that transmit pain signals, and gain-of-function Nav1.9 mutations have been associated with both painful and painless disorders. We initially determined that some Nav1.9 mutations are responsible for familial episodic pain syndrome observed in the Japanese population. We therefore generated model mice harboring one of the more painful Japanese mutations, R222S, and determined that dorsal root ganglia hyperexcitability was the cause of the associated pain.ANP-230 is a novel non-opioid drug with strong inhibitory effects on Nav1.7, 1.8 and 1.9, and is currently under clinical trials for patients suffering from familial episodic pain syndrome. However, little is known about its mechanism of action and effects on pain sensitivity.In this study, we therefore investigated the inhibitory effects of ANP-230 on the hypersensitivity of Nav1.9 p.R222S mutant model mouse to pain. In behavioral tests, ANP-230 reduced the pain response of the mice, particularly to heat or mechanical stimuli, in a concentration- and time-dependent manner. Furthermore, ANP-230 suppressed the repetitive firing of dorsal root ganglion neurons of these mutant mice. Our results clearly demonstrate that ANP-230 is an effective analgesic for familial episodic pain syndrome resulting from DRG neuron hyperexcitability, and that such analgesic effects are likely to be of clinical significance. |
| first_indexed | 2024-04-09T15:17:15Z |
| format | Article |
| id | doaj.art-82426671ec4a4a4290cc25e577c21d7f |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-04-09T15:17:15Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-82426671ec4a4a4290cc25e577c21d7f2023-04-29T14:56:42ZengElsevierHeliyon2405-84402023-04-0194e15423Reduced pain sensitivity of episodic pain syndrome model mice carrying a Nav1.9 mutation by ANP-230, a novel sodium channel blockerHiroko Okuda0Sumiko Inoue1Yoshihiro Oyamada2Akio Koizumi3Shohab Youssefian4Department of Pain Pharmacogenetics, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan; Corresponding author.Department of Pain Pharmacogenetics, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, JapanDepartment of Pain Pharmacogenetics, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan; AlphaNavi Pharma Inc., Osaka, 564-0053, JapanDepartment of Pain Pharmacogenetics, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan; Institute of Public Health and Welfare Research, Kyoto, 616-8141, Japan; Corresponding author. Department of Pain Pharmacogenetics, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.Department of Pain Pharmacogenetics, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan; Laboratory of Molecular Biosciences, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, JapanThe sodium channel Nav1.9 is expressed in the sensory neurons of small diameter dorsal root ganglia that transmit pain signals, and gain-of-function Nav1.9 mutations have been associated with both painful and painless disorders. We initially determined that some Nav1.9 mutations are responsible for familial episodic pain syndrome observed in the Japanese population. We therefore generated model mice harboring one of the more painful Japanese mutations, R222S, and determined that dorsal root ganglia hyperexcitability was the cause of the associated pain.ANP-230 is a novel non-opioid drug with strong inhibitory effects on Nav1.7, 1.8 and 1.9, and is currently under clinical trials for patients suffering from familial episodic pain syndrome. However, little is known about its mechanism of action and effects on pain sensitivity.In this study, we therefore investigated the inhibitory effects of ANP-230 on the hypersensitivity of Nav1.9 p.R222S mutant model mouse to pain. In behavioral tests, ANP-230 reduced the pain response of the mice, particularly to heat or mechanical stimuli, in a concentration- and time-dependent manner. Furthermore, ANP-230 suppressed the repetitive firing of dorsal root ganglion neurons of these mutant mice. Our results clearly demonstrate that ANP-230 is an effective analgesic for familial episodic pain syndrome resulting from DRG neuron hyperexcitability, and that such analgesic effects are likely to be of clinical significance.http://www.sciencedirect.com/science/article/pii/S2405844023026300Episodic pain syndromePain model miceSodium channel blockerNav1.9 voltage-gated sodium channelBehavioral experimentsElectrophysiology |
| spellingShingle | Hiroko Okuda Sumiko Inoue Yoshihiro Oyamada Akio Koizumi Shohab Youssefian Reduced pain sensitivity of episodic pain syndrome model mice carrying a Nav1.9 mutation by ANP-230, a novel sodium channel blocker Heliyon Episodic pain syndrome Pain model mice Sodium channel blocker Nav1.9 voltage-gated sodium channel Behavioral experiments Electrophysiology |
| title | Reduced pain sensitivity of episodic pain syndrome model mice carrying a Nav1.9 mutation by ANP-230, a novel sodium channel blocker |
| title_full | Reduced pain sensitivity of episodic pain syndrome model mice carrying a Nav1.9 mutation by ANP-230, a novel sodium channel blocker |
| title_fullStr | Reduced pain sensitivity of episodic pain syndrome model mice carrying a Nav1.9 mutation by ANP-230, a novel sodium channel blocker |
| title_full_unstemmed | Reduced pain sensitivity of episodic pain syndrome model mice carrying a Nav1.9 mutation by ANP-230, a novel sodium channel blocker |
| title_short | Reduced pain sensitivity of episodic pain syndrome model mice carrying a Nav1.9 mutation by ANP-230, a novel sodium channel blocker |
| title_sort | reduced pain sensitivity of episodic pain syndrome model mice carrying a nav1 9 mutation by anp 230 a novel sodium channel blocker |
| topic | Episodic pain syndrome Pain model mice Sodium channel blocker Nav1.9 voltage-gated sodium channel Behavioral experiments Electrophysiology |
| url | http://www.sciencedirect.com/science/article/pii/S2405844023026300 |
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