Vascular motion in the dorsal root ganglion sensed by Piezo2 in sensory neurons triggers episodic pain.

Summary

In mouse models of neuropathic pain, dynamic microvascular movements within injured dorsal root ganglia trigger episodic spontaneous pain via Piezo2 mechanotransduction in sensory neurons. Angiogenesis amplifies this phenomenon, and anti-VEGF therapy or targeting Piezo2 suppresses spontaneous pain and clustered neuronal firing.

Key Findings

• Dynamic movement of small blood vessels within injured DRG triggers spontaneous pain and clustered firing.
• Piezo2 in sensory neurons is required to sense vascular motion and mediate pain.
• Angiogenesis and increased pericytes amplify spontaneous pain; anti-VEGF blocks pain and clustered firing.
• Pharmacologic/mechanical induction of myogenic vascular responses increases spontaneous pain in mice.

Clinical Implications

While preclinical, the findings motivate development of peripherally targeted Piezo2 modulators and anti-angiogenic strategies for refractory spontaneous neuropathic pain, and encourage vascular-focused assessments in pain states.

Limitations

• Preclinical mouse data; human translatability remains to be established.
• Safety and specificity of Piezo2 or anti-angiogenic modulation for pain are unknown clinically.

Future Directions

Validate the mechanism in human DRG and patient-derived tissues; develop peripherally restricted Piezo2 modulators; test vascular-stabilizing or anti-angiogenic therapies in neuropathic pain models and early-phase trials.