ATP-releasing SWELL1 channel in spinal microglia contributes to neuropathic pain

Sci. Adv., 2023 · DOI: 10.1126/sciadv.ade9931 · Published: March 29, 2023

Simple Explanation

Following peripheral nerve injury, the body releases adenosine 5′-triphosphate (ATP). This ATP signals through purinergic receptors, which are crucial for activating spinal cord microglia and causing neuropathic pain. The mechanisms of this ATP release, however, are not well understood. This study shows that the volume-regulated anion channel (VRAC), specifically its essential subunit Swell1, acts as an ATP-releasing channel in microglia. This channel is activated by inflammatory mediator sphingosine-1-phosphate (S1P). Researchers identified dicumarol, an FDA-approved drug, as a potent VRAC inhibitor. Administering dicumarol alleviated nerve injury-induced pain in mice, suggesting VRAC in microglia is a therapeutic target for neuropathic pain.

Study Duration

Not specified

Participants

Mice with microglia-specific deletion of Swell1

Evidence Level

Not specified

Key Findings

1
SWELL1-dependent VRAC directly conducts and releases ATP from cells.
2
Microglia-specific deletion of Swell1 reduces nerve injury-induced increases in extracellular ATP, attenuates microgliosis and neuronal hyperactivity in the spinal dorsal horn, and alleviates neuropathic pain-like behaviors in mice.
3
Dicumarol, an FDA-approved drug, is identified as a potent and specific VRAC inhibitor, and its administration alleviates CCI-induced mechanical hypersensitivity in mice.

Research Summary

This study investigates the role of the volume-regulated anion channel (VRAC), specifically its essential subunit Swell1, in ATP release from spinal microglia and its contribution to neuropathic pain following peripheral nerve injury. The researchers found that Swell1-containing VRAC directly conducts and releases ATP, and that microglia-specific deletion of Swell1 reduces nerve injury-induced increases in extracellular ATP, attenuates microgliosis and neuronal hyperactivity, and alleviates neuropathic pain-like behaviors in mice. The study identifies dicumarol, an FDA-approved drug, as a potent and specific VRAC inhibitor, and demonstrates that its administration alleviates CCI-induced mechanical hypersensitivity in mice, suggesting VRAC as a potential therapeutic target for neuropathic pain.

Practical Implications

Therapeutic Target Identification

VRAC in microglia is a key spinal cord determinant of neuropathic pain and a potential therapeutic target for this debilitating disease.

Drug Repurposing

Dicumarol, an FDA-approved drug, can be repurposed as a novel treatment for neuropathic pain due to its potent and selective VRAC inhibition.

New Avenues for Pain Management

Targeting the Swell1 channel in microglia offers a new avenue for developing therapies for neuropathic pain and other diseases associated with abnormal VRAC activity.

Study Limitations

1
The Cx3cr1-Cre line used for microglia-specific deletion of Swell1 also drives Cre-mediated gene deletion in brain microglia and peripheral macrophages, potentially affecting results.
2
Potential off-target gene deletion in neurons for the Cx3cr1-Cre line cannot be completely excluded.
3
The study primarily focuses on male mice, and the sexual dimorphism observed suggests a need for further investigation into the role of microglial Swell1 in female mice.

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