Conditional knockout of Na1.6 in adult mice ameliorates neuropathic pain.

Voltage-gated sodium channels Na1.7, Na1.8 and Na1.9 have been the focus for pain studies because their mutations are associated with human pain disorders, but the role of Na1.6 in pain is less understood. In this study, we selectively knocked out Na1.6 in dorsal root ganglion (DRG) neurons, using Na1.8-Cre directed or adeno-associated virus (AAV)-Cre mediated approaches, and examined the specific contribution of Na1.6 to the tetrodotoxin-sensitive (TTX-S) current in these neurons and its role in neuropathic pain. We report here that Na1.6 contributes up to 60% of the TTX-S current in large, and 34% in small DRG neurons. We also show Na1.6 accumulates at nodes of Ranvier within the neuroma following spared nerve injury (SNI). Although Na1.8-Cre driven Na1.6 knockout does not alter acute, inflammatory or neuropathic pain behaviors, AAV-Cre mediated Na1.6 knockout in adult mice partially attenuates SNI-induced mechanical allodynia. Additionally, AAV-Cre mediated Na1.6 knockout, mostly in large DRG neurons, significantly attenuates excitability of these neurons after SNI and reduces Na1.6 accumulation at nodes of Ranvier at the neuroma. Together, Na1.6 in Na1.8-positive neurons does not influence pain thresholds under normal or pathological conditions, but Na1.6 in large Na1.8-negative DRG neurons plays an important role in neuropathic pain.