Chronic pain causes both physical suffering and comorbid mental symptoms such as anhedonia. However, the neural circuits and molecular mechanisms underlying these maladaptive behaviors remain elusive. Here using a mouse model, we report a pathway from vesicular glutamate transporter 3 neurons in the dorsal raphe nucleus to dopamine neurons in the ventral tegmental area (VGluT3^DRN→DA^VTA) wherein population-level activity in response to innocuous mechanical stimuli and sucrose consumption is inhibited by chronic neuropathic pain. Mechanistically, neuropathic pain dampens VGluT3^DRN → DA^VTA glutamatergic transmission and DA^VTA neural excitability. VGluT3^DRN → DA^VTA activation alleviates neuropathic pain and comorbid anhedonia-like behavior (CAB) by releasing glutamate, which subsequently promotes DA release in the nucleus accumbens medial shell (NAcMed) and produces analgesic and anti-anhedonia effects via D2 and D1 receptors, respectively. In addition, VGluT3^DRN → DA^VTA inhibition produces pain-like reflexive hypersensitivity and anhedonia-like behavior in intact mice. These findings reveal a crucial role for VGluT3^DRN → DA^VTA → D2/D1^NAcMed pathway in establishing and modulating chronic pain and CAB.

慢性疼痛会导致身体痛苦和共病精神症状，例如快感缺乏。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，我们使用小鼠模型，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的多巴胺神经元 (VGluT3 DRN} → DA ^VTA )的通路，其中群体水平的活动响应无害的机械刺激和蔗糖消耗被慢性神经性疼痛所抑制。从机制上讲，神经性疼痛会抑制 VGluT3 ^DRN  → DA ^VTA谷氨酸传递和 DA ^VTA神经兴奋性。VGluT3 ^DRN  → DA ^VTA激活通过释放谷氨酸减轻神经性疼痛和共病快感缺乏样行为 (CAB)，随后促进伏隔核内侧壳 (NAcMed) 中 DA 的释放，并通过 D2 和 D1 受体产生镇痛和抗快感缺乏作用，分别。此外，VGluT3 ^DRN  → DA ^VTA抑制会在完整小鼠中产生类似疼痛的反射性超敏反应和类似快感缺乏的行为。^{这些发现揭示了 VGluT3 DRN}  → DA ^VTA  → D2/D1 ^NAcMed通路在建立和调节慢性疼痛和 CAB 中的关键作用。