Analgesic actions of Intrathecal NaV 1.7 antisense in rats: loss of antagonist channel binding, message depletion, and neuraxial distribution of oligonucleotide Article Swipe
Kauê Franco Malange
,
Júlia Borges Paes Lemes
,
Briana Noble
,
Yuvicza Anchondo
,
Carlos E. Morado-Urbina
,
Sachin Jadhav
,
Sara A. Dochnal
,
Chiraag Kambalimath
,
Pedro Álvarez
,
Bethany Fitzsimmons
,
Curt Mazur
,
Holly Kordasiewicz
,
Kim Doré
,
Hien Zhao
,
Tony L. Yaksh
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.05.19.654680
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.05.19.654680
Background Genome targeting strategies to address NaV 1.7 mediated signaling in nociceptive afferents produce highly selective and persistent analgesic outcomes. Here, we analyze the concentration-dependent effects of the reduction of primary afferent NaV 1.7 channel expression by intrathecal delivery of an antisense oligonucleotide on pain behaviors and the covariance of Scn9a knock-down on NaV 1.7 message expression and channel binding. Methods Male Sprague-Dawley rats were implanted with lumbar intrathecal catheters and dosed with different NaV 1.7 ASO concentrations (100 to 3000 μg;10 μL). Pain behavior assays were conducted 0-28 days after ASO injections. Brain, spinal cords (SC) and dorsal root ganglia (DRGs) were collected. Quantification of ASO knock-down was assessed through RT-qPCR. NaV 1.7 expression was assessed by binding of NaV 1.7 fluorescent labeled antagonist (ATTO488PTx-II). Distribution studies were performed using anti-ASO antibody staining in brain, SCs and DRGs. Results NaV 1.7 message was detected in nerve, DRG and SC. Intrathecal ASO induced a concentration dependent gradient of knock down in DRGs (lumbar to cervical) of Scn9a mRNA and ATTO488PTx-II binding in small DRG neurons, and in spinal parenchyma, and a suppression of pain behaviors initiated by mechanical compression, inflammation and following intraplantar NaV1.7 agonist (OD1) or formalin. At 1000 µg, there was a 47% reduction in phase 2 flinching, a 60% reduction in DRG mRNA and a 36% reduction in ATTO488PTx-II DRG binding in comparison with mismatch controls. Although marked changes were seen at the sensory ganglia level and spinal dorsal horn, no changes in NaV 1.7 binding or mRNA were detected in sciatic nerves. Reduction in DRG message displayed a rostrocaudal gradient that corresponded with ASO distribution. Conclusions The study presents how NaV 1.7 ASOs reduce primary afferent channel binding through an effective knock-down on Scn9a mRNA, and channel binding leading to a covariate reduction in pain behavior.
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2025.05.19.654680
- https://www.biorxiv.org/content/biorxiv/early/2025/05/21/2025.05.19.654680.full.pdf
- OA Status
- green
- References
- 82
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4410579157
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Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4410579157Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2025.05.19.654680Digital Object Identifier
- Title
-
Analgesic actions of Intrathecal NaV 1.7 antisense in rats: loss of antagonist channel binding, message depletion, and neuraxial distribution of oligonucleotideWork title
- Type
-
preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2025Year of publication
- Publication date
-
2025-05-21Full publication date if available
- Authors
-
Kauê Franco Malange, Júlia Borges Paes Lemes, Briana Noble, Yuvicza Anchondo, Carlos E. Morado-Urbina, Sachin Jadhav, Sara A. Dochnal, Chiraag Kambalimath, Pedro Álvarez, Bethany Fitzsimmons, Curt Mazur, Holly Kordasiewicz, Kim Doré, Hien Zhao, Tony L. YakshList of authors in order
- Landing page
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https://doi.org/10.1101/2025.05.19.654680Publisher landing page
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https://www.biorxiv.org/content/biorxiv/early/2025/05/21/2025.05.19.654680.full.pdfDirect link to full text PDF
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YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
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https://www.biorxiv.org/content/biorxiv/early/2025/05/21/2025.05.19.654680.full.pdfDirect OA link when available
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Antagonist, Analgesic, Pharmacology, Intrathecal, Oligonucleotide, Distribution (mathematics), Chemistry, Medicine, Anesthesia, Receptor, Biochemistry, Mathematics, Gene, Mathematical analysisTop concepts (fields/topics) attached by OpenAlex
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0Total citation count in OpenAlex
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82Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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| referenced_works | https://openalex.org/W2558471778, https://openalex.org/W3105697612, https://openalex.org/W3095897671, https://openalex.org/W2916814039, https://openalex.org/W2147466595, https://openalex.org/W3007609503, https://openalex.org/W2602677564, https://openalex.org/W2044875580, https://openalex.org/W1559854530, https://openalex.org/W2085332935, https://openalex.org/W4365517825, https://openalex.org/W4283028809, https://openalex.org/W2763205332, https://openalex.org/W3114205754, https://openalex.org/W1527748034, https://openalex.org/W2914831630, https://openalex.org/W3044145717, https://openalex.org/W4323825289, https://openalex.org/W3136462045, https://openalex.org/W4317438751, https://openalex.org/W4205281492, https://openalex.org/W2584936131, https://openalex.org/W1989423171, https://openalex.org/W2172201406, https://openalex.org/W2256167805, https://openalex.org/W2123693245, https://openalex.org/W2171205074, https://openalex.org/W2125402042, https://openalex.org/W2298221259, https://openalex.org/W2143457814, https://openalex.org/W2069496882, https://openalex.org/W2753084136, https://openalex.org/W2912762225, https://openalex.org/W2053376101, https://openalex.org/W4403329692, https://openalex.org/W1977313312, https://openalex.org/W4312053829, https://openalex.org/W73139964, https://openalex.org/W2796308600, https://openalex.org/W4240181500, https://openalex.org/W2130496291, https://openalex.org/W2151515134, https://openalex.org/W2922222859, https://openalex.org/W4361249151, https://openalex.org/W2142947917, https://openalex.org/W2026551512, https://openalex.org/W1496508779, https://openalex.org/W2108114952, https://openalex.org/W2073360080, https://openalex.org/W2779347386, https://openalex.org/W2897315545, https://openalex.org/W3211786700, https://openalex.org/W3135015492, https://openalex.org/W3132028412, https://openalex.org/W4401710957, https://openalex.org/W1563910358, https://openalex.org/W2621235890, https://openalex.org/W4378516242, https://openalex.org/W2982482865, https://openalex.org/W2969792874, https://openalex.org/W2462655972, https://openalex.org/W4308367310, https://openalex.org/W2980602575, https://openalex.org/W2591728558, https://openalex.org/W4406990582, https://openalex.org/W4388640059, https://openalex.org/W2800339537, https://openalex.org/W1968809751, https://openalex.org/W2083848466, https://openalex.org/W2108328978, https://openalex.org/W1537638589, https://openalex.org/W4391058689, https://openalex.org/W2896902447, https://openalex.org/W1983539134, https://openalex.org/W2020021115, https://openalex.org/W2055555360, https://openalex.org/W2087444248, https://openalex.org/W2088672412, https://openalex.org/W2033425827, https://openalex.org/W2573178999, https://openalex.org/W2912647362, https://openalex.org/W2261280657 |
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| abstract_inverted_index.assays | 86 |
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| abstract_inverted_index.primary | 31, 279 |
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| abstract_inverted_index.RT-qPCR. | 112 |
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| abstract_inverted_index.antibody | 133 |
| abstract_inverted_index.assessed | 110, 117 |
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