Conditional knockout of NaV1.6 in adult mice ameliorates neuropathic pain

Voltage-gated sodium channels Na V 1.7, Na V 1.8 and Na V 1.9 have been the focus for pain studies because their mutations are associated with human pain disorders, but the role of Na V 1.6 in pain is less understood. In this study, we selectively knocked out Na V 1.6 in dorsal root ganglion (DRG) neurons, using Na V 1.8-Cre directed or adeno-associated virus (AAV)-Cre mediated approaches, and examined the specific contribution of Na V 1.6 to the tetrodotoxin-sensitive (TTX-S) current in these neurons and its role in neuropathic pain. We report here that Na V 1.6 contributes up to 60% of the TTX-S current in large, and 34% in small DRG neurons. We also show Na V 1.6 accumulates at nodes of Ranvier within the neuroma following spared nerve injury (SNI). Although Na V 1.8-Cre driven Na V 1.6 knockout does not alter acute, inflammatory or neuropathic pain behaviors, AAV-Cre mediated Na V 1.6 knockout in adult mice partially attenuates SNI-induced mechanical allodynia. Additionally, AAV-Cre mediated Na V 1.6 knockout, mostly in large DRG neurons, significantly attenuates excitability of these neurons after SNI and reduces Na V 1.6 accumulation at nodes of Ranvier at the neuroma. Together, Na V 1.6 in Na V 1.8-positive neurons does not influence pain thresholds under normal or pathological conditions, but Na V 1.6 in large Na V 1.8-negative DRG neurons plays an important role in neuropathic pain.