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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10161610/ https://www.ncbi.nlm.nih.gov/pubmed/37151704 http://dx.doi.org/10.1016/j.heliyon.2023.e15423 |
Sumario: | 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. |
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