前扣带皮层-下丘脑A11下行神经通路对三叉神经痛的调控作用及机制

三叉神经痛病因复杂且机制未明。多巴胺受体(D1/D2)参与三叉神经脊束核尾侧部(Sp5C)对三叉神经痛的调控。前扣带皮层(ACC)参与多种神经病理痛调控。下丘脑A11通过Sp5C的D2调控三叉神经痛。预实验显示：ACC谷氨酸能神经元下行投射至下丘脑A11，A11区GABA神经元表达AMPA受体，A11多巴胺神经元表达GABAA受体并下行投射至Sp5C；兴奋ACC谷氨酸能神经元加重三叉神经痛；在CCI-IoN模型中，Sp5C的DARPP-T34磷酸化水平增加，兴奋D2降低DARPP-T34磷酸化水平。据此推测ACC谷氨酸能神经元通过下丘脑A11区GABA神经元、多巴胺神经元参与Sp5C对三叉神经痛的调控，Sp5C的D2-DARPP信号途径介导其机制。我们拟利用转基因小鼠、光/化学遗传学等技术探讨ACC-下丘脑A11下行神经通路对三叉神经痛的调控及机制，为防治三叉神经痛提供依据。

Trigeminal neuropathic pain is a physically and emotionally debilitating condition. However, its underlying mechanisms remain unclear. As an important neurotransmitter in the top-down pain modulation system, dopamine exerts its function by binding to two types of dopamine receptors named D1-like and D2-like receptors. These receptors express in trigeminal nucleus and may exert different modulation on pain. Previous studies have demonstrated that the dopamine receptors D1 and D2 in the spinal trigeminal nucleus caudalis (Sp5C) are involved in the regulation of trigeminal neuropathic pain. In addition, evidence has reported that neuropathic pain threshold decreases by stimulation anterior cingulate cortex (ACC). By using retrograde tracing, we have revealed that hypothalamic A11 projects to the Sp5C in the mouse. Specifically, the descending pathway from hypothalamic A11 to the Sp5C originates mainly from dopaminergic neurons, which are closely associated with pain modulation. Our preliminary data showed that glutamatergic neurons projected to hypothalamic A11. Meanwhile, we observed that AMPA receptor subunit GluA1 expressed in GABAergic neurons in A11, while GABAA receptor expressed in dopaminergic neurons. Further study showed that activation of glutamatergic neuron in ACC enhanced CCI-IoN induced neuropathic pain. Besides that, a small molecule DARPP protein showed increased phosphorylation at Thr34 sites. However, this phosphorylation decreased after stimulation on D2 receptor. Therefore, we hypothesize that ACC-hypothalamic A11 descending pathway can regulates CCI-IoN induced trigeminal neuropathic pain. To address this hypothesis, we will use transgenic mice combined with optogenetic/chemogenetic techniques, pain behavioral testing, in vivo calcium imaging to investigate the effects of ACC-hypothalamic A11 descending pathway on CCI-IoN induced neuropathic pain and its underlying mechanisms. The present study will provide new thoughts for the treatment of trigeminal neuropathic pain.