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

Abstract

Voltage-gated sodium channels NaV1.7, NaV1.8 and NaV1.9 have been the focus for pain studies because their mutations are associated with human pain disorders, but the role of NaV1.6 in pain is less understood. In this study, we selectively knocked out NaV1.6 in dorsal root ganglion (DRG) neurons, using NaV1.8-Cre directed or adeno-associated virus (AAV)-Cre mediated approaches, and examined the specific contribution of NaV1.6 to the tetrodotoxin-sensitive (TTX-S) current in these neurons and its role in neuropathic pain. We report here that NaV1.6 contributes up to 60% of the TTX-S current in large, and 34% in small DRG neurons. We also show NaV1.6 accumulates at nodes of Ranvier within the neuroma following spared nerve injury (SNI). Although NaV1.8-Cre driven NaV1.6 knockout does not alter acute, inflammatory or neuropathic pain behaviors, AAV-Cre mediated NaV1.6 knockout in adult mice partially attenuates SNI-induced mechanical allodynia. Additionally, AAV-Cre mediated NaV1.6 knockout, mostly in large DRG neurons, significantly attenuates excitability of these neurons after SNI and reduces NaV1.6 accumulation at nodes of Ranvier at the neuroma. Together, NaV1.6 in NaV1.8-positive neurons does not influence pain thresholds under normal or pathological conditions, but NaV1.6 in large NaV1.8-negative DRG neurons plays an important role in neuropathic pain.

• Authors: Lubin Chen, Jianying Huang, Peng Zhao, Anna-Karin Persson, Fadia B Dib-Hajj, Xiaoyang Cheng, Andrew Tan, Stephen G Waxman, Sulayman D Dib-Hajj
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 3845 (03 01 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29497094 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• NAV1.3 Voltage-Gated Sodium Channel
• NAV1.6 Voltage-Gated Sodium Channel
• NAV1.8 Voltage-Gated Sodium Channel
• Scn8a protein, mouse
• Sodium Channel Blockers
• Voltage-Gated Sodium Channels
• Tetrodotoxin

Topics

• Animals
• Female
• Ganglia, Spinal (metabolism)
• Hyperalgesia (genetics, metabolism)
• Male
• Mice
• Mice, Knockout
• NAV1.3 Voltage-Gated Sodium Channel (metabolism)
• NAV1.6 Voltage-Gated Sodium Channel (genetics, metabolism, physiology)
• NAV1.8 Voltage-Gated Sodium Channel (metabolism)
• Nerve Tissue (metabolism)
• Neuralgia (genetics, metabolism)
• Neurons (metabolism)
• Patch-Clamp Techniques
• Sodium Channel Blockers (pharmacology)
• Tetrodotoxin (pharmacology)
• Voltage-Gated Sodium Channels (genetics, metabolism)