The transcription factor Y-box binding protein 3 contributes to mechanical allodynia and anxiety-like behavior in trigeminal neuralgia by transcriptionally triggering period circadian regulator 1 in primary sensory neurons.

Nerve injury-mediated alterations in gene expression in trigeminal ganglion (TG) neurons contribute to nociceptive hypersensitivity. A transcription factor "Y-box binding protein 3 (YBX3)" regulates gene expression, however, its role in neuropathic pain remains unknown. We report that YBX3 is predominantly expressed in TG neurons, where it coexists with period circadian regulator 1 (PER1). Chronic constriction of the unilateral infraorbital nerve (CCI-ION) leads to levels of Ybx3 mRNA and YBX3 protein in injured TG increased in a time-dependent manner. Blocking this increase through microinjection of siRNA-YBX3 into the injured TG attenuated the CCI-ION-induced upregulation of PER1, as well as the maintenance of nociceptive hypersensitivities and anxiety-like behavior. Conversely, mimicking this increase by microinjecting AAV9-YBX3 into the TG elevated PER1 expression, and induced ongoing pain in naïve mice. Additionally, both PER1 isoforms at ZT8 exhibited higher expression levels compared to those at ZT20 after CCI-ION. Mechanistically, YBX3 bound to the promoter of Per1 and increased its expression in injured TG neurons. These findings suggest that YBX3 is a key regulator in mechanical allodynia and anxiety-like behaviors in trigeminal neuralgia. The YBX3-PER1 pathway in TG may serve as a potential therapeutic target for trigeminal neuralgia (TN) and pain induced anxiety-like behaviors.