A glutamatergic brain neural circuit is critical for modulating trigeminal neuropathic pain

Trigeminal neuropathic pain is a predominant symptom in patients with trigeminal neuralgia. However, the underlying neural circuit mechanism is still elusive. In this study, we investigated the role of a brain neural circuit in the modulation of trigeminal neuropathic pain. We used "Targeted Recombination in Active Populations" to identify activated neurons in brain structures. Anterograde and retrograde viral tracing combined with immunofluorescence staining was used to validate the activated neurons-involved neuronal pathway. We performed optogenetic stimulation and behavioral observation to dissect the brain neural circuitry that underlies the modulation of trigeminal neuropathic pain. We further conducted dual-color fiber photometry to analyze dynamic neurotransmitter release and real-time neuronal activity while observing pain behaviors simultaneously. We observed that mouse neurons in the anterior paraventricular nucleus of thalamus were activated specifically by chronic constriction injury of the infraorbital nerve. We further observed that specifical excitation or silencing of the activated neurons bidirectionally modulated the nerve injury-caused trigeminal neuropathic pain in mice. More importantly, optogenetic activation of the brain neural circuit from anterior paraventricular nucleus of thalamus to anterior cingulate cortex exacerbated such pain and this effect was blocked by an N-methyl-d-aspartate receptor antagonist. Meanwhile, optogenetic activation of this neural circuit markedly increased glutamate release and enhanced neuronal activity in the anterior cingulate cortex. Our results suggest that the identified brain neural circuit could be targeted to develop a novel neuromodulation therapy for trigeminal neuropathic pain.