# TRPM3 mediates spontaneous pain and mechanical allodynia in a mouse model of chronic orofacial neuropathy

## TL;DR

The study shows that TRPM3 is crucial for chronic orofacial pain in mice and suggests TRPM3 inhibitors could be a new treatment for trigeminal neuropathic pain.

## Contribution

The novel contribution is identifying TRPM3 as a key mediator of trigeminal neuropathic pain and demonstrating its potential as a therapeutic target.

## Key findings

- TRPM3 is essential for spontaneous pain and mechanical allodynia in trigeminal neuropathy.
- TRPM3 antagonists like primidone and isosakuranetin reverse neuropathic pain symptoms.
- Transcriptomic changes in trigeminal ganglia are not affected by TRPM3 absence.

## Abstract

Trigeminal nerve injury can lead to chronic and difficult-to-treat orofacial neuropathic pain. Here, we uncover a key role for the cation channel TRPM3 in the chronic constriction injury of the infraorbital nerve (IoN-CCI) mouse model of trigeminal neuropathic pain. Wild-type (WT) mice develop spontaneous pain and mechanical allodynia for up to 6 weeks following IoN-CCI, whereas Trpm3−/− mice do not develop such symptoms. Using longitudinal RNA sequencing (RNA-seq) analysis, we obtain a detailed time course of transcriptome alterations in trigeminal ganglia during progression of the IoN-CCI model; notably, gene expression regulation is not different between WT and Trpm3−/− mice. Two structurally distinct TRPM3 antagonists, primidone and isosakuranetin, effectively reverse spontaneous pain and mechanical allodynia, whereas mavatrep, a potent TRPV1 antagonist, is without analgesic effect. These data indicate that TRPM3 is essential for ongoing pain and allodynia following trigeminal nerve injury, making it a potential target for treating trigeminally mediated neuropathic pain.

•TRPM3 is required for ongoing pain and mechanical allodynia after trigeminal injury•Injury-induced transcriptomic changes in trigeminal ganglia are TRPM3 independent•TRPM3 antagonists reduce trigeminal neuropathic pain; TRPV1 blockade is ineffective•Association between human trigeminal neuralgia and rare variants in the TRPM3 gene

TRPM3 is required for ongoing pain and mechanical allodynia after trigeminal injury

Injury-induced transcriptomic changes in trigeminal ganglia are TRPM3 independent

TRPM3 antagonists reduce trigeminal neuropathic pain; TRPV1 blockade is ineffective

Association between human trigeminal neuralgia and rare variants in the TRPM3 gene

Deseure et al. demonstrate that the cation channel TRPM3 is essential for the development of spontaneous pain or mechanical hypersensitivity in a mouse model of chronic trigeminal neuropathic pain. Their findings indicate that pharmacological TRPM3 inhibition may represent a therapeutic target to treat trigeminal neuralgia and related neuropathies in patients.