Chronic pain causes both physical suffering and comorbid mental disorders such as depression. However, the neural circuits and molecular mechanisms underlying these maladaptive behaviors remain elusive. Here, we report a pathway from vesicular glutamate transporter3 neurons in the dorsal raphe nucleus to dopamine neurons in the ventral tegmental area (VGluT3DRN→DAVTA), of which population activity in response to innocuous mechanical stimuli and sucrose consumption, is respectively inhibited and attenuated by chronic neuropathic pain. Mechanistically, neuropathic pain dampens VGluT3DRN→DAVTA glutamatergic transmission and DAVTA neural excitability. VGluT3DRN→DAVTA activation alleviates neuropathic pain and comorbid depression-like behavior (CDB) by releasing glutamate, which subsequently promotes DA release in the nucleus accumbens medial shell (NAcMed) and produces analgesia and antidepressant effects via D2 and D1 receptors, respectively. In addition, VGluT3DRN→DAVTA inhibition produces pain-like hypersensitivity and depression-like behavior in healthy mice. These findings reveal a novel VGluT3DRN→DAVTA→D2/D1NAcMed pathway in establishing and modulating chronic pain and comorbid depressive-like behavior.

中文翻译：

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用于神经性疼痛和共病抑郁样行为调节的谷氨酸能 DRN-VTA 通路

慢性疼痛会导致身体痛苦和并发精神障碍，例如抑郁症。然而，这些适应不良行为背后的神经回路和分子机制仍然难以捉摸。在这里，我们报告了从中缝背核中的囊泡谷氨酸转运蛋白 3 神经元到腹侧被盖区 (VGluT3DRN→DAVTA) 中的多巴胺神经元的通路，其中响应无害机械刺激和蔗糖消耗的种群活动分别被抑制和减弱慢性神经性疼痛。从机制上讲，神经性疼痛会抑制 VGluT3DRN→DAVTA 谷氨酸能传递和 DAVTA 神经兴奋性。VGluT3DRN→DAVTA 激活通过释放谷氨酸来减轻神经性疼痛和共病抑郁样行为 (CDB)，随后促进伏隔核内侧壳 (NAcMed) 中的 DA 释放，并分别通过 D2 和 D1 受体产生镇痛和抗抑郁作用。此外，VGluT3DRN→DAVTA 抑制会在健康小鼠中产生疼痛样超敏反应和抑郁样行为。这些发现揭示了一种新的 VGluT3DRN→DAVTA→D2/D1NAcMed 通路在建立和调节慢性疼痛和共病抑郁样行为中的作用。