外周TRPC3/6通道通过调节BDNF的释放介导机械性痛觉敏化的作用及机制研究

机械性痛觉敏化是慢性病理性疼痛患者的主要症状之一，然而，关于机械性痛觉敏化的分子机制尚未完全阐明。TRPC通道赋予脊椎动物细胞对机械刺激的敏感性，其中TRPC3和TRPC6蛋白在感觉神经元中高表达，参与正常的机械传导，且在炎症时表达显著上调。然而，TRPC3/6通道是否以及如何介导病理痛情况下的机械性超敏反应亟待解决。本项目拟利用DRG伤害性神经元中特异性敲低TRPC3/6通道，明确外周DRG伤害性神经元中TRPC3/6通道对于机械性痛敏的作用，并探讨其对DRG伤害性神经元以及脊髓背角突触传递活动的影响，揭示其通过调节BDNF释放介导病理情况下机械性痛觉敏化的作用机制。该问题的阐明不仅有助于揭示外周DRG伤害性神经元中TRPC3/6通道在机械性痛觉敏化形成中的功能意义，还有助于揭示慢性痛机械性痛觉敏化的的细胞分子机制，从而为治疗慢性病理性疼痛患者提供一种副作用小的镇痛新策略。

Patients with tissue injury or inflammation often experience aberrant mechanical pain hypersensitivity. Despite this, the molecular mechanisms underlying this mechanical distortion are poorly understood. Canonical transient receptor potential (TRPC) channels are shown to confer sensitivity to mechanical stimulation in vertebrate cells. Amongst which, TRPC3 and TRPC6 proteins, coassembling as heterotetrameric channels, are highly expressed in sensory neurons and implicated in normal mechanotransduction，and are significantly upregulated at DRG and spinal cord upon inflammation. However, whether and how thes channels mediate mechanical pain hypersensitivity need to be solved. The purpose of this project is to investigate the role of TRPC3/6 channels in peripheral DRG nociceptive neurons on mechanical pain hypersensitivity by specifically knocking down TRPC3/6 channels in DRG nociceptive neurons, and to explore its effect on DRG nociceptive neurons activity and synaptic transmission in spinal dorsal horn, so as to reveal the mechanism of TRPC3/6 channels mediated mechanical pain hypersensitivity in pathological condition by regulating BDNF release. The elucidation of this problem not only helps to reveal the functional significance of TRPC3/6 channels in peripheral DRG nociceptive neurons in the formation of mechanical pain hypersensitivity, but also helps to reveal molecular mechanism of mechanical pain hypersensitivity in chronic pain, so as to provide a new strategy for the treatment of patients with chronic pathological pain with least side effects.