中脑腹侧被盖区-海马通路多巴胺能神经元对术后慢性痛的调控机制

Chronic pain is a common complication after surgery, and the underlying mechanism is not yet clear. Dopamine receptor 1 (D1)-positive neurons in hippocampal CA1 area participate in the initiation, maintenance and regulation of pain. Kalirin-7/Rac1 signaling contributes to pain chronification by regulating synaptic plasticity and LTP formation. Our preliminary data showed that dopaminergic neurons in VTA area and D1 receptor in hippocampal CA1 were activated during stress-induced postoperative chronic pain. In addition, hippocampal Kalirin-7/Rac1 signaling pathway was also involved in pain chronification. Based on this, we hypothesize that dopaminergic projection from VTA to hippocampus may contribute to stress-induced postoperative pain chronification by D1/Kalirin-7/Rac1 signaling pathway. To address this hypothesis, we will develop a mouse model of postoperative pain chronification induced by stress, and combine with transgenic mice, optogenetic and chemogenetic techniques, electrophysiological recording, and molecular biology methods to explore the role of dopaminergic neurons in the VTA-hippocampus projection in postoperative management. This will provide important evidence for prevention and treatment of chronic pain in clinic.

慢性痛是术后常见并发症，其机制尚不清楚。海马CA1区多巴胺受体1(D1)阳性神经元参与疼痛的发生、维持和调控。Kalirin-7/Rac1信号通过调控突触可塑性和LTP等机制介导慢性痛的形成机制。我们预实验表明应激导致的术后慢性痛过程中，VTA区多巴胺能神经元和海马CA1区D1受体被激活、Kalirin-7/Rac1信号通路也被激活。我们据此推测在应激致术后慢性痛机制中，VTA-海马神经通路多巴胺能神经元通过D1/Kalirin-7/Rac1信号途径参与并介导术后慢性痛产生和调控机制。我们拟通过制备应激致术后疼痛慢性化小鼠模型，利用转基因小鼠和光/化学遗传学技术、电生理记录、分子生物学等技术，探讨VTA-海马通路多巴胺能神经元在术后慢性痛中的作用机制，为临床防治术后慢性痛提供思路和依据。

慢性痛是术后常见并发症，其机制尚不清楚。海马神经元参与疼痛的产生和调制作用,多巴胺受体1(D1)参与海马CA1区神经元介导的疼痛调控机制。Kalirin-7/Rac1信号通过调控突触可塑性和LTP等机制介导慢性痛的形成机制。我们的实验表明应激导致的术后慢性痛过程中，VTA区多巴胺能神经元和海马CA1区D1受体被激活、Kalirin-7/Rac1信号通路也被激活。我们据此推测在应激致术后慢性痛机制中，VTA-海马神经通路多巴胺能神经元通过D1/Kalirin-7/Rac1信号途径参与并介导术后慢性痛产生和机制。在本项研究中我们制备应激致术后疼痛慢性化小鼠模型，利用转基因小鼠和光/化学遗传学技术、电生理记录、分子生物学等技术，发现术前应激可以引起VTA区多巴胺能神经元兴奋，引起VTA投射至海马CA1区神经末梢释放多巴胺增多，激活D1受体，继而激活Kalirin-7以及下游信号，引起疼痛加重和疼痛时间延长。这一发现有可能帮助临床医生寻求新的治疗措施防治术后慢性疼痛的发生，也为筛选治疗慢性疼痛药物提供参考。