A <i>Tac1</i> ‐Expressing Brainstem Pathway Underlies the Pathogenesis of Trigeminal Neuralgia

Trigeminal neuralgia (TN) is widely recognized to be one of the most severe pain disorders, severely affects the life quality of patients. However, the neuronal mechanisms underlying TN pathogenesis remain largely unknown. Here, we identify a periphery-to-brain neural circuit that governs TN development in mice. Tachykinin 1 (Tac1)-expressing parabrachial nucleus (PBN^Tac1) neurons show heightened stimulus-evoked responses, and chemogenetic inhibition of these neurons effectively prevents TN development. Furthermore, PBN^Tac1 neurons receive projections from the caudal part of the spinal trigeminal nucleus (Sp5C), and PBN-projecting Sp5C neurons are essential for TN-induced pain hypersensitivity. Remarkably, PBN-projecting Sp5C neurons predominantly express Tac1, and knockdown Tac1 gene in these neurons significantly attenuates TN-induced pain hypersensitivity. Through retrograde viral tracing and electrophysiological recordings, we demonstrate that Tac1-expressing Sp5C neurons directly relay signals from the trigeminal ganglion (TG) to the PBN. Collectively, our findings unveil a critical TG-Sp5C^Tac1-PBN^Tac1 pathway that drives the TN pathogenesis.