生长抑素参与脊髓痒觉环路的机制研究

Itch, especially chronic itch damages the patient's quality of life. Unfortunately, there are few preventive measures and therapeutic options for those that suffer from severe chronic itch. The main reason is that until recently, little is known about signaling mechanisms underlying chronic itch. Our optogenetic results showed that activation of somatostatin (Sst) neurons in the spinal cord induced itch behavior. Sst antagonist significantly decreased GRP or Nppb-evoked scratching. Scratching behavior elicited by injection of histamine, chloroquine or other itch reagents was also significantly decreased in Sstf/f；TRPV 1 Cre mice. However, the role of Sst in spinal itch neural circuit and the mechanism remain unclear. The present study will use Sstf/f；TRPV1 Cre mice、Sstf/f；Lbx1 Cre mice、Sst Cre: Ai9 mice，combined with virus injection, molecular biological methods, pharmacological and behavioral methods, electrophysiological methods to examine the interaction of Sst with excitatory itch pathway and the connection of Sst with itch-related neurons in the spinal cord. To detect the impact of knock out Sst in DRG or spinal cord on itch behavior and the plasticity of Sst neurons in chronic itch sensation. Such experiments will help to reveal the new mechanism on itch, and ultimately provide novel therapies to alleviate chronic itch.

瘙痒，尤其是慢性瘙痒严重影响患者的生活质量，目前尚缺乏有效的防治措施，究其原因是痒觉传递与调控机制尚未阐明。我们前期光遗传学结果显示激活脊髓生长抑素（somatostatin, Sst）神经元可诱发痒行为；Sst拮抗剂降低GRP和Nppb诱发的搔抓次数；条件性剔除背根神经节内Sst，组胺、氯喹等致痒物质引起的搔抓次数降低。但Sst在脊髓痒觉环路中的具体作用环节和机制并不清楚。本项目将运用Sstf/f；TRPV1 Cre小鼠、Sstf/f；Lbx1 Cre小鼠、Sst Cre: Ai9等小鼠，结合病毒注射、分子生物学、行为药理学、电生理学等技术，研究Sst与兴奋性痒觉通路的作用关系及与痒觉神经元的形态学联系；探讨条件性剔除背根神经节或脊髓内Sst对痒觉传递的影响及痒状态下Sst神经元的可塑性变化。旨在为阐明痒觉的环路机制提供新思路，为开发有效的瘙痒防治药物提供新靶点。

痒觉是一种引起抓挠欲望的不愉快的感觉和情绪体验，慢性瘙痒严重影响患者的生活质量，目前尚缺乏有效的防治措施，究其原因是痒觉传递与调控机制尚未阐明。本项目按计划顺利完成，获得大量创新性的结果。运用生长抑素（somatostatin, Sst）条件性剔除小鼠和Sst Cre、dynorphin Cre等转基因小鼠，结合形态学、分子生物学、电生理学、行为药理学、光遗传学和化学遗传学等技术，以背根神经节和脊髓为靶区，探讨了生长抑素能神经元在脊髓背角痒觉神经环路中的作用。研究了Sst与兴奋性痒觉通路的作用关系及与痒觉神经元的形态学联系；观察了条件性剔除背根神经节和脊髓内Sst对痒觉传递的影响及痒状态下Sst神经元的可塑性变化。Sst在DRG与Nppb大量共存；光遗传学结果显示激活生长抑素神经元可诱发痒行为；Sst拮抗剂降低GRP和Nppb诱发的搔抓次数；激活脊髓背角强啡肽能神经元可抑制由致痒物质引起的搔抓反应，Sst通过作用于脊髓背角强啡肽能神经元进而参与了抑制性痒觉通路，并与脊髓水平兴奋性痒觉通路有相互作用关系；条件性剔除脊髓和背根神经节的Sst，致痒物质引起的搔抓次数降低。上述研究结果为阐明痒觉的环路机制提供了新思路，为开发有效的瘙痒防治药物提供了新靶点。