Sodium Channel Na_v1.7 Is Essential for Lowering Heat Pain Threshold after Burn Injury

Abstract

Marked hypersensitivity to heat and mechanical (pressure) stimuli develop after a burn injury, but the neural mechanisms underlying these effects are poorly understood. In this study, we establish a new mouse model of focal second-degree burn injury to investigate the molecular and cellular basis for burn injury-induced pain. This model features robust injury-induced behavioral effects and tissuespecific altered cytokine profile, but absence of glial activation in spinal dorsal horn. Three voltage-gated sodium channels, Na v 1.7, Na v 1.8, and Na v 1.9, are preferentially expressed in peripheral somatosensory neurons of the dorsal root ganglia (DRGs) and have been implicated in injury-induced neuronal hyperexcitability. Using knock-out mice, we provide evidence that Na v 1.7 selectively contributes to burn-induced hypersensitivity to heat, but not mechanical, stimuli. After burn model injury, wild-type mice display increased sensitivity to heat stimuli, and a normally non-noxious warm stimulus induces activity-dependent Fos expression in spinal dorsal horn neurons. Strikingly, both effects are absent in Na v 1.7 conditional knock-out (cKO) mice. Furthermore, burn injury increases density and shifts activation of tetrodotoxin-sensitive currents in a hyperpolarized direction, both pro-excitatory properties, in DRG neurons from wild-type but not Na v 1.7 cKO mice. We propose that, in sensory neurons damaged by burn injury to the hindpaw, Na v 1.7 currents contribute to the hyperexcitability of sensory neurons, their communication with postsynaptic spinal pain pathways, and behavioral thresholds to heat stimuli. Our results offer insights into the molecular and cellular mechanisms of modality-specific pain signaling, and suggest Na v 1.7-blocking drugs may be effective in burn patients.

Evaluation of behavior and expression of NaV1.7 in dorsal root ganglia after sciatic nerve compression and application of nucleus pulposus in rats

“…Furthermore, NaV1.7 has an important role in nerve injury pain. Shields et al [37] reported that NaV1.7 in DRG are implicated in injury-induced neuronal hyperexcitability in a burn-injury model. They suggested NaV1.7-blocking drugs may be effective in burn patients.…”

A pharmacological and transcriptomic approach to exploring novel pain targets

“…This model appears suitable for analgesic efficacy profiling of novel treatments that may provide improved management approaches for this under-treated and difficult-to-manage condition. In contrast to previously reported mouse models 187 , this model causes a superficial or first-degree burn, without the presence of blisters or broken skin, while still producing robust mechanical and thermal allodynia as well as detectable differences in weight bearing behaviour.…”

“…As Na V 1.7 knockout animals did not develop burn-induced thermal allodynia but exhibited robust burn-induced mechanical allodynia 187 , this chapter further explored the contribution of various Na V isoforms in burn-induced thermal and mechanical allodynia. TTX was examined first in thermal allodynia and was found to be effective, suggesting that TTX-s Na V isoforms are involved in burn-induced thermal allodynia.…”

“…Cancer-induced bone pain and resultant gait abnormalities were also not significantly affected by Na V 1.7 knockout in all peripheral neurons 186 . There are also pain conditions that are only partially alleviated by Na V 1.7 knockout in Na V 1.8-positive neurons, such as allodynia following a burn injury 187 .…”

“…A peripheral mild burn injury was produced in wild-type male C57BL/6 mice based on methods used in a previous mouse model 187 and in rat models [294][295][296] . Exposure of the left hind paw in mice to a metal surface set at a temperature of 52.5°C for 25 seconds resulted in a first-degree or superficial burn (for detailed location see Appendix 3.5), as evidenced by the immediate development of localised redness and swelling, without the presence of blisters.…”