Sensory neuron-specific block of multifaceted sodium channels mitigates neuropathic pain behaviors of osteoarthritis.

OBJECTIVE: Multiple voltage-gated sodium channels (Na(V)s) 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 Na(V) 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 Na(V) inhibitory peptide aptamer, termed Na(V)iPA1, that has a multipronged feature of inhibiting tetrodotoxin-sensitive Na(V)1.7, 1.6, 1.1, and 1.3, characterized in our recent report. Adeno-associated virus-encoded Na(V)iPA1 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 Na(V)iPA1 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 Na(V)iPA1 expression normalized action potential firing of the PSNs from MIA animals, suggesting that Na(V)iPA1 attenuated pain behavior by, at least in part, reversing neuronal hyperexcitability. CONCLUSION: Together, these results support that (1) Na(V)s in peripheral sensory pathways contribute to MIA-OA pain pathogenesis and (2) Na(V)iPA1 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.