5-HT3受体介导Ca2+/CaMKII信号通路在帕金森病疼痛中的作用机制研究

Pain is one of the most common non-motor symptoms in patients with Parkinson's disease (PD). It can occur before motor symptoms and is also one of the major causes of misdiagnosis of early PD. The rate of the diagnosis of PD-related pain is low. There is no uniform treatment standard for pain in PD. There are also few studies on the pathogenesis of pain in PD. The exact pathogenesis mechanism of pain in PD is unknown. Dopaminergic treatment can only relieve pain in some of the PD patients, suggesting that systems other than dopaminergic system, are also involved in the regulation of pain in PD patients. Our previous study found impaired 5-serotonin (5-HT) neurons in the rostral ventromedial medulla in the 6-OHDA-induced PD rat model and decreased 5-HT nerve fibers and 5-HT content projected to the spinal dorsal horn. 5-HT3A receptor inhibitors can relieve pain in PD model rats. Based on this, we will use molecular techniques and electrophysiological techniques to study the facilitating effect of 5-HT receptors on PD related pain in combination with pharmacological methods. We will further use 6-OHDA-induced PD rat model to study the role of 5-HT3 receptors mediated Ca2 + / CaMKII Signaling involved in PD-related pain in the spinal dorsal horn. The research of this project will provide a theoretical basis for clarifying the pathogenesis mechanism of pain in PD.

疼痛是困扰帕金森病（Parkinson's disease , PD）患者常见的非运动症状之一，可出现于运动症状之前，也是导致早期PD被误诊的重要原因之一。目前PD相关疼痛的诊断率低，治疗无统一标准。关于PD相关疼痛机制的研究也较少，确切机制不明。多巴胺能药物只能改善部分PD患者疼痛，提示多巴胺能以外的系统也参与了PD相关疼痛的调节。我们的前期研究发现在6-OHDA诱导的PD大鼠模型中，延髓头端腹内侧5-HT能神经元受损、投射到脊髓背角的5-HT能神经纤维以及5-HT含量减少。5-HT3A受体抑制剂可以缓解PD模型大鼠的疼痛。本研究将在此基础上，运用分子生物学及电生理等技术，结合药理学方法研究不同亚型5-HT受体对PD疼痛的下行易化作用，深入研究脊髓背角中5-HT3受体介导Ca2+/CaMKII信号通路参与PD相关疼痛的机制。本项目的研究将为明确PD相关疼痛机制提供理论依据。

帕金森病（PD）疼痛是困扰PD患者常见的非运动症状，也是重要的早期症状之一。目前关于PD疼痛机制的研究较少，确切机制尚不清楚。现有研究提示延髓和脑桥背盖部出现的路易体病变与运动症状之前出现的非运动症状密切相关。临床发现多巴胺能药物并不能改善所有的PD患者疼痛，表明多巴胺以外的系统也参与了PD疼痛的调节。位于低位脑干中缝核内的5-HT能神经元下行纤维主要投射到脊髓参与痛觉调制。脊髓中通过5-HT3受体发挥下行通路对痛觉具有抑制、易化双重调节作用。本项目拟利用6-OHDA诱导的PD大鼠模 型和A53T小鼠从整体水平研究脊髓背角中5-HT3受体参与PD疼痛的机制。本项目采用辐射热-缩爪法和vonfrey法检测大鼠热痛阈和机械痛阈的变化，发现6-OHDA大鼠无论辐射热痛阈还是机械痛阈值都是降低的，提示6-OHDA大鼠存在痛觉过敏；鞘内注射5-HT3拮抗剂Ondansetron 100 μg后随着时间的增加6-OHDA大鼠的痛阈明显上升，机械痛阈值缓解的时间较为短暂，而辐射热甩尾痛阈值的缓解可持续120 min之久；鞘内注射5-HT1受体拮抗剂WAY100635和激动剂8-OH，并在大鼠完全苏醒后按照时间点进行机械痛阈和热痛阈值的测定。结果表示，无论是激动剂还是拮抗剂，对6-OHDA大鼠的痛阈没有改变；脊髓背角中的5-HT3受体可能通过增强受体敏感性的方式参与PD疼痛的发生；我们通过WB检测了脊髓背角中CaMKII和p-CaMKII的表达，发现6-OHDA大鼠中p-CaMKII表达显著增加而总的CaMKII表达没有显著变化。本项目研究结果提示，非多巴胺能系统，尤其是5-HT3受体相关系统参与了PD相关疼痛的发生。通过本研究将为PD 相关疼痛治疗新靶点提供依据。