Spinal cord retinoic acid receptor signaling gates mechanical hypersensitivity in neuropathic pain

Neuron, 2022 · DOI: 10.1016/j.neuron.2022.09.027 · Published: December 21, 2022

Simple Explanation

This study investigates the molecular mechanisms underlying spinal disinhibition after nerve injury, focusing on neuropathic pain and mechanical hypersensitivity. The researchers found that nerve injury triggers a reduction of inhibitory outputs from specific interneurons in the spinal cord. This reduction leads to hyperactivation of the spinal cord nociceptive pathway, which results in mechanical hypersensitivity. The retinoic acid receptor RARα was identified as a key mediator of this synaptic disinhibition. Blocking RARα in specific neurons or using an RARα antagonist prevented the development of mechanical hypersensitivity, suggesting RARα is a potential target for neuropathic pain treatment.

Study Duration

3 weeks

Participants

Mice

Evidence Level

Not specified

Key Findings

1
Spared nerve injury (SNI) induces mechanical hypersensitivity and neuropathic pain through homeostatic reduction of inhibitory outputs from dorsal horn parvalbumin-positive (PV+) interneurons.
2
The retinoic acid receptor RARα is identified as the key molecular mediator for synaptic disinhibition in spinal PV+ neurons after nerve injury.
3
Deletion or inhibition of RARα in spinal PV+ neurons prevents SNI-induced mechanical hypersensitivity, indicating RARα as a crucial effector for neuropathic pain.

Research Summary

This study demonstrates that spared nerve injury (SNI) leads to mechanical hypersensitivity and neuropathic pain by triggering homeostatic reduction of inhibitory outputs from dorsal horn parvalbumin-positive (PV+) interneurons. The retinoic acid receptor RARα is identified as a key molecular mediator for this synaptic disinhibition. Deletion of RARα in spinal PV+ neurons or application of an RARα antagonist in the spinal cord prevented the development of SNI-induced mechanical hypersensitivity. These results identify RARα as a crucial molecular effector for neuropathic pain and a potential target for its treatment.

Practical Implications

Therapeutic Target

RARα signaling in spinal PV+ neurons represents a potential therapeutic target for the treatment of neuropathic pain.

Critical Period

A critical period exists after nerve injury during which RARα-mediated homeostatic modulation of dorsal horn circuit function can be targeted for effective therapeutic intervention.

Central Sensitization Mechanism

The study elucidates a key mechanism of central sensitization where peripheral nerve injury triggers homeostatic synaptic compensation in spinal dorsal horn circuits, causing redirection of tactile sensory signals into nociceptive circuits.

Study Limitations

1
The study primarily uses a mouse model, and the findings may not directly translate to human neuropathic pain.
2
Pharmacological inhibition of RARα inhibits RARα in all cell types, limiting specificity.
3
The study identifies RARα as a key player, but additional signaling mechanisms involved in homeostatic synaptic plasticity need further exploration.

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