Abstract
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.