TRPC3和TRPC6通道诱致慢性痛痛觉敏化的作用及作用机制

近年来TRPC3和TRPC6通道在中枢神经系统的定位分布和功能逐渐被揭示。然而，除了中枢神经系统以外，TRPC3和TRPC6还大量表达在痛信息传导路，尤其是第一站的伤害性感受器上，并且在炎症或损伤后其活动显著增强。我们最新研究显示敲除TRPC3和TRPC6可显著抑制炎症或损伤诱致的痛敏，提示TRPC3和TRPC6在病理状态下可能具有致痛敏作用。但是，其发挥致痛敏作用的细胞分子机制尚不清楚。为此，本项目拟利用TRPC3和TRPC6基因敲除小鼠模型这一特异性工具，综合分子生物学、电生理学、行为学等方法探讨TRPC3和TRPC6在病理状态下的致痛敏作用、揭示其通过介导外周敏化、初级传入突触功能可塑性及结构可塑性改变而诱致致痛敏作用的细胞分子机制，以期阐明TRPC3和TRPC6在痛觉信息传递和痛敏形成过程中的功能意义，为研发针对TRPC3和TRPC6通道的新型镇痛药提供重要的科学依据和理论指导。

Recently, TRPC channels, especially TRPC3 and TRPC6 subtypes have been shown to be expressed in the central nervous system and involved in a number of biological functions including neuronal proliferation/development, cell survival, axon guidance and cognition. However, besides the central nervous system, TRPC3 and TRPC6 channels are also widely expressed in the pain pathways, especially in the first site of pain signals processing---nociceptors. After injury or inflammation, the expression of TRPC3 and TRPC6 in nociceptors was shown to be up-regulated. Most recently, our preliminary data showed that deletion of TRPC3 and TRPC6 were able to reduce the pain hypersensitivity caused by injury or inflammation, suggesting that TRPC3 and TRPC6 may play a pronociceptive role in the pathological states. However, the cellular and molecular mechanisms underlying its pronociceptive effect remains elusive. Therefore, by using a combination of transgenic mouse models, electrophysiological, calcium imaging, behavioral as well as biochemical methods, the present study aims to: 1) to investigate whether TRPC3 and TRPC6 play a pronociceptive role in the pathological states; 2) to explore the cellular and molecular mechanisms underlying the role of TRPC3 and TRPC6 in the peripheral sensitization; 3) to explore the cellular and molecular mechanisms by which TRPC3 and TRPC6 modulate functional and structural synaptic plasticity of synapse between nociceptive primary afferents and spinal lamina I neurons. Understanding the above questions may help to unravel the functional significance of TRPC3 and TRPC6 in the pain signals transmission and pain hypersensitivity. New insights derived these advances are expected to expediate development of novel analgesics acting at TRPC3 and TRPC6 for the treatment of chronic pain.