A TRPV4-dependent neuroimmune axis in the spinal cord promotes neuropathic pain

J Clin Invest, 2023 · DOI: https://doi.org/10.1172/JCI161507 · Published: March 1, 2023

Simple Explanation

Microglia, resident immune cells in the spinal cord, play a key role in the development of neuropathic pain. This study found that a protein called TRPV4, present in microglia, contributes to this process. The researchers discovered that by blocking TRPV4 in mice, they could reduce neuropathic pain. This suggests TRPV4 could be a new target for pain relief. Further investigation revealed that TRPV4 influences how microglia behave, affecting the activity of nerve cells in the spinal cord and promoting pain. The study identifies a molecular pathway involving TRPV4 and a protein called lipocalin-2 (LCN2) that drives neuropathic pain.

Study Duration

Not specified

Participants

Mice

Evidence Level

Not specified

Key Findings

1
TRPV4 is functionally expressed in spinal resident microglia and its expression is increased in a mouse model of spared nerve injury (SNI).
2
Genetic ablation or pharmacological blockade of TRPV4 markedly attenuated neuropathic pain-like behaviors in a mouse model of spared nerve injury.
3
Microglia-expressed TRPV4 mediated microglial activation and proliferation and promoted functional and structural plasticity of excitatory spinal neurons through release of lipocalin-2.

Research Summary

Microglia, resident macrophages of the CNS, are essential to brain development, homeostasis, and disease. Microglial activation and proliferation are hallmarks of many CNS diseases, including neuropathic pain. Genetic ablation or pharmacological blockade of transient receptor potential vanilloid type 4 (TRPV4) markedly attenuated neuropathic pain-like behaviors in a mouse model of spared nerve injury. Our results suggest that microglial TRPV4 channels reside at the center of the neuroimmune axis in the spinal cord, which transforms peripheral nerve injury into central sensitization and neuropathic pain, thereby identifying TRPV4 as a potential new target for the treatment of chronic pain.

Practical Implications

Targeted Pain Therapies

The identification of TRPV4 as a key mediator in neuropathic pain opens avenues for developing targeted therapies that could reduce reliance on opioids.

Neuroimmune Axis Modulation

Understanding the neuroimmune axis and the role of microglia in chronic pain can lead to new strategies for modulating immune responses in the spinal cord to alleviate pain.

Biomarker Development

LCN2's involvement in TRPV4-mediated spinal synaptic plasticity suggests it could serve as a biomarker for assessing the severity and progression of neuropathic pain.

Study Limitations

1
The study is conducted on mice, and the results may not directly translate to humans.
2
The precise role of sex in TRPV4-dependent neuropathic pain requires further investigation.
3
The underlying mechanisms through which LCN2 differentially regulates synaptic alterations in the hippocampus and spinal cord are still unknown.

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