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Abstract
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.
Highlights
Among chronic pain conditions, trigeminal neuralgia (TN) is considered to be one of the most severe [9]
The present study shows that partial transection of the infraorbital nerve (pT-ION)-induced allodynia and anxiety-like behaviors can be differentially modulated by altering Tacr3 expression and subsequent lateral habenula (LHb) function
We found that Tacr3 in the left LHb was among the top 20 most strongly down-regulated differentially expressed genes (DEGs), and the downregulation of Tacr3 was seen in the LHb and not in other negative emotion-related brain areas such as the anterior cingulate cortex (ACC), prefrontal cortex (PFC), and hippocampus
Summary
Trigeminal neuralgia (TN) is considered to be one of the most severe [9]. TN is a neuropathic disorder causing excruciating unilateral orofacial pain and mood disorders [27]. It is very common for people with TN to show abnormal anxiety before washing their face or eating food [9], and negative emotions subsequent to chronic pain can further exacerbate the pain sensation [3]. The LHb has been shown to be involved in detecting and processing nociceptive stimulation in acute and chronic pain [37]. It is reported that about two thirds of the LHb neurons show a response to nociceptive stimulation, and among these neurons both excitatory and inhibitory patterns have been recorded depending on the intensity of the stimuli [5]. Whether and how the LHb participates in the pathogenesis of pain and anxiety in TN is unknown
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