Neuronal and Molecular Mechanisms Underlying Chronic Pain and Depression Comorbidity in the Paraventricular Thalamus

Author:

Cui Mengqiao,Ji Ran,Song Lingzhen,Wang Xianlei,Pan Xiaoyuan,Han YiORCID,Zhai Xiaojing,Ai Lin,Zhang Wenxin,Xie An,Wu Zhou,Song Weiyi,Yang Jun-Xia,Hu Ankang,Liu HeORCID,Cao Jun-LiORCID,Zhang Hongxing

Abstract

Patients with chronic pain often develop comorbid depressive symptoms, which makes the pain symptoms more complicated and refractory. However, the underlying mechanisms are poorly known. Here, in a repeated complete Freund's adjuvant (CFA) male mouse model, we reported a specific regulatory role of the paraventricular thalamic nucleus (PVT) glutamatergic neurons, particularly the anterior PVT (PVA) neurons, in mediating chronic pain and depression comorbidity (CDC). Our c-Fos protein staining observed increased PVA neuronal activity in CFA-CDC mice. In wild-type mice, chemogenetic activation of PVA glutamatergic neurons was sufficient to decrease the 50% paw withdrawal thresholds (50% PWTs), while depressive-like behaviors evaluated with immobile time in tail suspension test (TST) and forced swim test (FST) could only be achieved by repeated chemogenetic activation. Chemogenetic inhibition of PVA glutamatergic neurons reversed the decreased 50% PWTs in CFA mice without depressive-like symptoms and the increased TST and FST immobility in CFA-CDC mice. Surprisingly, in CFA-CDC mice, chemogenetically inhibiting PVA glutamatergic neurons failed to reverse the decrease of 50% PWTs, which could be restored by rapid-onset antidepressant S-ketamine. Further behavioral tests in chronic restraint stress mice and CFA pain mice indicated that PVA glutamatergic neuron inhibition and S-ketamine independently alleviate sensory and affective pain. Molecular profiling and pharmacological studies revealed the 5-hydroxytryptamine receptor 1D (Htr1d) in CFA pain-related PVT engram neurons as a potential target for treating CDC. These findings identified novel CDC neuronal and molecular mechanisms in the PVT and provided insight into the complicated pain neuropathology under a comorbid state with depression and related drug development.

Funder

STI2030-Major Projects

MOST | National Natural Science Foundation of China

Jiangsu Province Innovative and Entrepreneurial Team Program

Jiangsu Province Key R&D Program Social Development Project

MOST | NSFC | NSFC-Zhejiang Joint Fund | 浙江省科学技术厅 | Natural Science Foundation of Zhejiang Province

Priority Academic Program Development of Jiangsu Higher Education Institutions

China Postdoctoral Science Foundation

Xuzhou Medical University start-up grant for excellent scientist

Postgraduate Research and Practice Innovation Program of Jiangsu Province

Science and Technology Department of Jiangsu Province

Publisher

Society for Neuroscience

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