Trigeminal root demyelination is sufficient to induce trigeminal neuralgia-like facial pain in adult rodents

Background
Current etiology-centered management guidelines have not brought about satisfactory outcomes for trigeminal neuralgia patients. Therefore, there is an urgent call for pathology-targeted diagnosis and treatment modalities for this intractable disease. Trigeminal root demyelination has been frequently shown or suggested in trigeminal neuralgia patients of diverse etiologies and then naturally regarded as the common pathological cause of this disease. However, this causal relationship has never been validated so far with success in either preclinical or clinical studies. One of the key obstacles is that trigeminal root demyelination per se has not been proven as yet to be sufficient to induce trigeminal neuralgia-like facial pain in animals.

Methods
Trigeminal root demyelination was directly induced by MRI-informed stereotactic microinjection of (1) myelin-destructive lysophosphatidylcholine into both extrapontine and intrapontine trigeminal roots of adult rats and (2) recombinant adeno-associated virus that genetically ablates myelin-forming oligodendrocytes via apoptosis into trigeminal root entry zones of adult mice. Long-lasting asymmetric eyelid contraction and asymmetric cluster face-stroking were adopted as the affective and motivational behavioral proxies to assess facial pain. More importantly, carbamazepine versus pregabalin treatment and chemical silencing of primary nociceptive afferents were used to ascertain the resemblance of facial pain in rodent models to trigeminal neuralgia in patients.

Results
Chemically or viral genetically induced demyelination in trigeminal root entry zones were shown to induce facial pain behaviors in adult rats and mice. More importantly, facial pain in these rodent models was shown to resemble patient trigeminal neuralgia in terms of the preferred responsiveness to carbamazepine and the unique requirement of primary nociceptive afferents. Moreover, focal demyelination in adult rat intrapontine trigeminal roots was also shown to induce trigeminal neuralgia-like facial pain.

Conclusions
Trigeminal root demyelination is sufficient to induce trigeminal neuralgia-like facial pain in adult rodents. Our noteworthy findings would support trigeminal root demyelination as the common pathological cause of trigeminal neuralgia. This advancement will promote pathological conceptualization and clinical management of this etiologically heterogeneous disease as a unified entity of demyelinating disorders. Meanwhile, a group of simple and reliable pathological rodent models were provided for further investigations into trigeminal neuralgia.