Ectopic expression of Nav1.7 in spinal dorsal horn neurons induced by NGF contributes to neuropathic pain in a mouse spinal cord injury model

Frontiers in Molecular Neuroscience, 2023 · DOI: 10.3389/fnmol.2023.1091096 · Published: March 3, 2023

Spinal Cord Injury Neurology Pain Management

Simple Explanation

Neuropathic pain (NP) after spinal cord injury (SCI) is a long-term problem, but the reasons why are not well understood. This study found that SCI causes Nav1.7 to be produced in spinal dorsal horn (SDH) neurons and increases Nav1.7 in dorsal root ganglion (DRG) neurons in mice. The study also found that a drug that blocks Nav1.7 and can cross the blood-brain barrier (GNE-0439) was better at reducing NP in SCI mice than a drug that cannot cross the blood-brain barrier (PF-05089771). Finally, the study showed that NGF and JUN, which can increase Nav1.7, were increased after SCI in SDH and DRG neurons. Blocking Nav1.7 in both peripheral and spinal neurons reduced mechanical pain in SCI mice.

Study Duration

Not specified

Participants

Adult (8–11 weeks) C57BL/6N mice

Evidence Level

Original Research

Key Findings

1
SCI induces ectopic expression of Nav1.7 in SDH neurons, making them hypersensitive and contributing to central sensitization and spontaneous/walking-evoked mechanical pain.
2
BBB-permeable Nav1.7 inhibitor GNE-0439 shows better efficacy in attenuating NP in SCI mice compared to the BBB non-permeable inhibitor PF-05089771, suggesting a role for ectopic Nav1.7 expression in SDH.
3
SCI upregulates NGF and its downstream JUN in both SDH and DRG neurons, leading to increased Nav1.7 expression, indicating a potential therapeutic target for SCI-induced NP.

Research Summary

This study investigates the mechanisms behind neuropathic pain (NP) induced by spinal cord injury (SCI) in mice, focusing on the role of Nav1.7, a voltage-gated sodium channel. The findings demonstrate that SCI leads to ectopic expression of Nav1.7 in spinal dorsal horn (SDH) neurons and upregulation in dorsal root ganglion (DRG) neurons. The study suggests that BBB permeable Nav1.7 blockers might relieve NP in patients with SCI and that blocking the upregulation of Nav1.7 in the early stage of SCI via selective inhibition of the downstream signaling pathways of NGF or Nav1.7-targeted RNA drugs could be a strategy for therapy of SCI-induced NP.

Practical Implications

Therapeutic Target Identification

Targeting Nav1.7, NGF, and JUN could be a promising therapeutic strategy for SCI-induced neuropathic pain.

Drug Development

BBB-permeable Nav1.7 blockers may offer more effective pain relief for SCI patients.

Early Intervention

Blocking Nav1.7 upregulation in the early stages of SCI may prevent the development of chronic neuropathic pain.

Study Limitations

1
The study is limited to a mouse model, and findings may not directly translate to humans.
2
The exact mechanisms by which NGF activates Nav1.7 transcription require further investigation.
3
The short half-life of GNE-0439 in mice necessitates the development of more stable and sustained-release formulations.

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