Trigeminal neuralgia (TN) is debilitating and is usually accompanied by mood disorders. The lateral habenula (LHb) is considered to be involved in the modulation of pain and mood disorders, and the present study aimed to determine if and how the LHb participates in the development of pain and anxiety in TN. To address this issue, a mouse model of partial transection of the infraorbital nerve (pT-ION) was established. pT-ION induced stable and long-lasting primary and secondary orofacial allodynia and anxiety-like behaviors that correlated with the increased excitability of LHb neurons. Adeno-associated virus (AAV)-mediated expression of hM4D(Gi) in glutamatergic neurons of the unilateral LHb followed by clozapine-N-oxide application relieved pT-ION-induced anxiety-like behaviors but not allodynia. Immunofluorescence validated the successful infection of AAV in the LHb, and microarray analysis showed changes in gene expression in the LHb of mice showing allodynia and anxiety-like behaviors after pT-ION. Among these differentially expressed genes was Tacr3, the downregulation of which was validated by RT-qPCR. Rescuing the downregulation of Tacr3 by AAV-mediated Tacr3 overexpression in the unilateral LHb significantly reversed pT-ION-induced anxiety-like behaviors but not allodynia. Whole-cell patch clamp recording showed that Tacr3 overexpression suppressed nerve injury-induced hyperexcitation of LHb neurons, and western blotting showed that the pT-ION-induced upregulation of p-CaMKII was reversed by AAV-mediated Tacr3 overexpression or chemicogenetic inhibition of glutamatergic neurons in the LHb. Moreover, not only anxiety-like behaviors, but also allodynia after pT-ION were significantly alleviated by chemicogenetic inhibition of bilateral LHb neurons or by bilateral Tacr3 overexpression in the LHb. In conclusion, Tacr3 in the LHb plays a protective role in treating trigeminal nerve injury-induced allodynia and anxiety-like behaviors by suppressing the hyperexcitability of LHb neurons. These findings provide a rationale for suppressing unilateral or bilateral LHb activity by targeting Tacr3 in treating the anxiety and pain associated with TN.

中文翻译：

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在三叉神经痛小鼠模型中，外侧汉逊管中的Tacr3差异性调节口面部异常性疼痛和焦虑样行为。

三叉神经痛（TN）使人衰弱，通常伴有情绪障碍。人们认为外侧ha（LHb）参与了疼痛和情绪障碍的调节，本研究旨在确定LHb是否以及如何参与TN的疼痛和焦虑症的发展。为了解决这个问题，建立了眶下神经部分横断的小鼠模型（pT-ION）。pT-ION诱导稳定和持久的原发性和继发性口面性异常性疼痛以及与LHb神经元兴奋性增加相关的焦虑样行为。腺相关病毒（AAV）介导的单侧LHb的谷氨酸能神经元中hM4D（Gi）的表达，然后施加氯氮平-N-氧化物可缓解pT-ION诱导的焦虑样行为，但不能减轻异常性疼痛。免疫荧光验证了AH在LHb中的成功感染，并且微阵列分析显示pT-ION后小鼠LHb基因表达的变化显示出异常性疼痛和焦虑样行为。在这些差异表达的基因中有Tacr3，其下调已通过RT-qPCR验证。在单侧LHb中通过AAV介导的Tacr3过表达来挽救Tacr3的下调，可显着逆转pT-ION诱导的焦虑样行为，但不会改变异常性疼痛。全细胞膜片钳记录表明Tacr3过表达抑制了神经损伤诱导的LHb神经元过度兴奋，而Western印迹显示pT-ION诱导的p-CaMKII上调被AAV介导的Tacr3过表达或对谷氨酸能神经元的化学生成抑制所逆转在LHb中。而且，不仅像焦虑一样的行为，但通过化学抑制双侧LHb神经元或双侧Tacr3在LHb中的过度表达，pT-ION后的异常性疼痛也明显减轻。总之，LHb中的Tacr3通过抑制LHb神经元的过度兴奋性，在治疗三叉神经损伤引起的异常性疼痛和焦虑样行为中起保护作用。这些发现为通过靶向Tacr3治疗TN相关的焦虑和疼痛提供了抑制单侧或双侧LHb活性的理由。LHb中的Tacr3通过抑制LHb神经元的过度兴奋性，在治疗三叉神经损伤引起的异常性疼痛和焦虑样行为中起保护作用。这些发现为通过靶向Tacr3治疗TN相关的焦虑和疼痛提供了抑制单侧或双侧LHb活性的理由。LHb中的Tacr3通过抑制LHb神经元的过度兴奋性，在治疗三叉神经损伤引起的异常性疼痛和焦虑样行为中起保护作用。这些发现为通过靶向Tacr3治疗TN相关的焦虑和疼痛提供了抑制单侧或双侧LHb活性的理由。