Sensory neuron–specific block of multifaceted sodium channels mitigates neuropathic pain behaviors of osteoarthritis
Objective:. Multiple voltage-gated sodium channels (NaVs) in the peripheral sensory neurons (PSNs) regulate action potentials and their dysfunction contributes to the pain pathogenesis of osteoarthritis (OA). A combined block of multiple NaV subtypes selectively in the PSNs may, therefore, represent...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer
2025-08-01
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| Series: | PAIN Reports |
| Online Access: | http://journals.lww.com/painrpts/fulltext/10.1097/PR9.0000000000001288 |
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| Summary: | Objective:. Multiple voltage-gated sodium channels (NaVs) in the peripheral sensory neurons (PSNs) regulate action potentials and their dysfunction contributes to the pain pathogenesis of osteoarthritis (OA). A combined block of multiple NaV subtypes selectively in the PSNs may, therefore, represent an effective analgesic approach in OA painful neuropathy.
Methods:. To test this hypothesis, we generated recombinant adeno-associated virus (AAV) encoding a potent NaV inhibitory peptide aptamer, termed NaViPA1, that has a multipronged feature of inhibiting tetrodotoxin-sensitive NaV1.7, 1.6, 1.1, and 1.3, characterized in our recent report. Adeno-associated virus-encoded NaViPA1 was delivered into the ipsilateral lumbar 4/5 dorsal root ganglia of rats 2 weeks after induction of knee monoiodoacetate-OA (MIA-OA) and evoked and spontaneous sensory behaviors were followed in 6 weeks.
Results:. Expression of NaViPA1 selective in the PSNs produced significant and comparable mitigations of evoked and spontaneous pain behavior and reversal of weight-bearing asymmetry in both male and female MIA-OA rats. Whole-cell current-clamp recordings showed that AAV-mediated NaViPA1 expression normalized action potential firing of the PSNs from MIA animals, suggesting that NaViPA1 attenuated pain behavior by, at least in part, reversing neuronal hyperexcitability.
Conclusion:. Together, these results support that (1) NaVs in peripheral sensory pathways contribute to MIA-OA pain pathogenesis and (2) NaViPA1 is a promising analgesic lead that, combined with AAV-targeted delivery to pathological sensory ganglia, may be a viable peripherally selective PSN-targeting strategy in mitigating chronic MIA-OA pain behaviors. |
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| ISSN: | 2471-2531 |