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.
Highlights
spared nerve injury (SNI) and reduces NaV1.6 accumulation at nodes of Ranvier at the neuroma
Our results suggest that approximately 80% of the voltage-dependent sodium currents in NaV1.8-positive large dorsal root ganglion (DRG) neurons are TTX-S, and more than one half of the TTX-S current is carried by NaV1.6 sodium channels
NaV1.6 has recently been implicated in pain in humans[27], and in animal models[23,24,25,26], the specific contribution of NaV1.6 to the TTX-S current in DRG neurons and to neuropathic pain in knockout models has far not been reported
Summary
SNI and reduces NaV1.6 accumulation at nodes of Ranvier at the neuroma. Together, NaV1.6 in NaV1.8positive neurons does not influence pain thresholds under normal or pathological conditions, but. Activation of NaV1.1 using a spider toxin has been shown to produce robust pain behavior and profound hypersensitivity to mechanical stimuli, establishing the first evidence linking NaV1.1 to acute pain and mechanical allodynia[22]. Local knockdown of NaV1.6 using siRNA has been shown to reduce spontaneous neuronal activity and nociceptive behaviors in rodent models of chronic pain[25,26]. Our data show that NaV1.6 contributes a substantial fraction of the TTX-S current in both small and large DRG neurons and manifests a long half-life at nodes of Ranvier in vivo, and that NaV1.6 has limited role in acute nociception, it contributes to the development and maintenance of neuropathic pain behavior following spared nerve injury (SNI)
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