Authors: Wu S-J et al.
Anesthesiology, November 2025. DOI: 10.1097/ALN.0000000000005854
Summary
This mechanistic neuroscience study examined how a specific subset of primary sensory neurons—those capable of synthesizing GABA and expressing the vesicular GABA transporter Vgat—gate mechanical pain transmission in mice. While most dorsal root ganglion (DRG) neurons are glutamatergic and excitatory, these Vgat-positive neurons represent a small but functionally distinct inhibitory population.
Using multiple methods including viral tracing, immunohistochemistry, electrophysiology, optogenetics, chemogenetics, and behavioral assays in Vgat-Cre mice, the investigators mapped the spinal circuits innervated by Vgat+ neurons. They discovered that Vgat+ primary sensory neurons have dual functionality: their central terminals form inhibitory synapses onto somatostatin-positive (SOM+) excitatory interneurons, while also forming excitatory glutamatergic connections onto local GABAergic interneurons, producing feed-forward inhibition.
Together these pathways create a microcircuit that suppresses mechanical pain transmission. In healthy mice, activation of Vgat+ neurons prevented aversive or pain-like responses to both innocuous and noxious mechanical stimuli. After peripheral nerve injury, inhibitory signaling from these neurons to SOM+ interneurons decreased, correlating with mechanical hypersensitivity. Optogenetic or chemogenetic activation of Vgat+ neurons restored inhibition and reduced nerve-injury–induced mechanical pain behavior.
Key Points
• A subset of DRG neurons synthesizes GABA and expresses Vgat, enabling inhibitory signaling.
• These neurons form both direct inhibitory and indirect feed-forward inhibitory connections in the spinal cord.
• This dual pathway suppresses mechanical pain transmission under normal conditions.
• Peripheral nerve injury disrupts this inhibitory control, contributing to mechanical allodynia.
• Activating Vgat+ neurons reduces mechanical hypersensitivity, suggesting a potential therapeutic target.
Thank you for allowing us to use this article from Anesthesiology.