前扣带回皮质-脊髓通路在神经病理性疼痛大鼠负性情绪与疼痛感知调节中的作用研究

Patients with neuropathic pain often suffer from negative emotions, such as depression and anxiety. The interweaving of negative emotion and pain perception may explain why neuropathic pain is intractable. To explore the regulatory role of negative emotion on pain perception is important for understanding the mechanisms underlying neuropathic pain. Negative emotions are mainly mediated by pathological changes in the brain regions such as the anterior cingulate cortex (ACC). Recent studies have shown that ACC can send direct descending projecting terminals to the dorsal horn of the spinal cord (SDH), which forms the ACC-SDH descending facilitation pathway. In our preliminary study, we have found that blocking the activity of ACC-SDH projection neurons can reverse the facilitation effect of negative emotions on neuropathic pain. Thus, we hypothesized that ACC-SDH pathway may mediate the regulation effect of negative emotion on pain perception and play a critical role in the pathogenesis of neuropathic pain. In the present study, we employ optogenetics and chemogenetics technique, neural tracer technique, electrophysiology and other experimental approach to clarify the role of ACC-SDH pathway in the negative emotion regulation of pain perception, and further explore the neural, cellular and molecular mechanisms involved in this pathway. Based on this present study, the involvement of negative emotion regulating pain perception in neuropathic pain will be explored, which would shed light on the treatment of neuropathic pain.

神经病理性疼痛常导致病人产生抑郁和焦虑等负性情绪。负性情绪与疼痛感知交织形成恶性循环，是神经病理性疼痛迁延不愈的原因之一。探索负性情绪对疼痛感知的调控作用是神经病理性疼痛机制研究中的重要环节。负性情绪主要由前扣带回皮质（ACC）等脑区的病理改变所介导。最新研究显示，ACC可发出纤维投射至脊髓背角(SDH)，形成ACC-SDH通路易化疼痛的形成。我们前期也发现，抑制ACC-SDH投射神经元活性可以逆转负性情绪对神经病理性疼痛的易化。据此我们提出假说：ACC-SDH通路可能介导了负性情绪对疼痛感知的调节过程，在神经病理性疼痛发病中起到重要作用。本项目将采用光和化学遗传学、神经示踪、电生理等技术手段，明确ACC-SDH通路在负性情绪调节疼痛感知中的作用，并深入分析该通路中所涉及的神经、细胞和分子等机制。通过以上研究，进一步揭示负性情绪调节疼痛感知在神经病理性疼痛中的作用机制，为治疗提供理论依据。

神经病理性疼痛常导致病人产生抑郁和焦虑等负性情绪。负性情绪与疼痛感知交织形成恶性循环，是神经病理性疼痛迁延不愈的原因之一。探索负性情绪对疼痛感知的调控作用是神经病理性疼痛机制研究中的重要环节。本研究首先利用神经示踪实验发现，负性情绪刺激神经病理性大鼠可以易化神经病理性疼痛的发展，并且激活ACC-SDH直接投射系统。随后，我们利用化学遗传实验发现，抑制ACC-SDH投射神经元活性可以逆转负性情绪对神经病理性疼痛的易化，并且我们还发现，BDNF可以作为神经调节因子，调节ACC-SDH环路易化神经病理性过程。最后我们利用RNA-Seq实验，发现ACC-SDH通路主要通过调节脊髓水平LAMB1的表达，进而调控突触结构可塑性参与负性情绪易化疼痛过程。通过以上研究，我们进一步完善负性情绪调控疼痛感知的神经环路机制，为治疗难治性神经病理性疼痛提供理论依据及潜在靶点，具有重要的临床意义。