谷氨酸受体上调前扣带回兴奋性与可塑性造成慢性胰腺炎持续性疼痛的机制研究

As a common disease of the pancreas, chronic pancreatitis has intractable pain as its dominated symptom. Major theories emerged to explain the pathogenesis of chronic pancreatitis have their limitation. Due to lack of fully understanding about the pathogenesis of pain, there is no satisfactory treatment. It is recognized that the structure and function of visceral pain pathway are changed in chronic pancreatitis patients. Our previous study demonstrated that changes of glutamate receptors in anterior cingulate cortex (ACC) resulted in excitability elevations in rat model of chronic pancreatitis, which could be reversed by NMDA antagonist. In the current project, we will validate the hypothesis that chronic pancreatitis may induce the changes of plasticity and excitability of ACC by long-term nociceptive afferent, which could be the explanation of the abnormal pain-related behaviors in addition to the local and systemic hypersensitivity. Investigation for the effects of the NMDA-CaMKII-AMPA pathway and PKMζ-AMPA pathway on the quantity and function of glutamate receptors will also be carried out by molecular biological and electrophysiological methods. The project may provide further understanding of pain mechanisms in chronic pancreatitis, and will help to identify novel clinical therapeutic targets.

慢性胰腺炎是常见的胰腺疾病之一，频繁发作性或持续性疼痛是慢性胰腺炎最主要且棘手的症状。基于解剖改变的多种理论不能全面解释慢性胰腺炎的慢性疼痛机制。由于缺乏对慢性胰腺炎疼痛的发病机制的深入认识，目前尚无满意的治疗手段。研究发现慢性胰腺炎时中枢神经系统的内脏痛觉传导通路的结构与功能发生变化。本研究组前期研究发现慢性胰腺炎大鼠模型前扣带回的谷氨酸受体变化导致兴奋性升高，拮抗相应受体可逆转痛觉高敏。本申请项目拟通过分子生物学和电生理的方法，验证慢性胰腺炎的各种致痛因素长期影响下前扣带回的突触可塑性和兴奋性发生变化，由此导致胰腺局部、胃肠道和躯体痛觉敏感性升高和痛觉情绪行为的异常。并探索在上述中枢改变过程中，前扣带回的NMDA-CaMKII-AMPA途径和PKMζ-AMPA途径是否通过影响谷氨酸受体数量和功能起关键介导作用。本研究将为进一步认识慢性胰腺炎疼痛机制，寻找临床治疗靶标提供帮助。

慢性胰腺炎是常见的胰腺疾病之一，频繁发作性或持续性疼痛是慢性胰腺炎最主要且棘手的症状。基于解剖改变的多种理论不能全面解释慢性胰腺炎的慢性疼痛机制。由于缺乏对慢性胰腺炎疼痛的发病机制的深入认识，目前尚无满意的治疗手段。研究发现慢性胰腺炎时中枢神经系统的内脏痛觉传导通路的结构与功能发生变化。本研究组前期研究发现慢性胰腺炎大鼠模型前扣带回的谷氨酸受体变化导致兴奋性升高，拮抗相应受体可逆转痛觉高敏。本项目通过分子生物学和电生理的方法，验证慢性胰腺炎的各种致痛因素长期影响下前扣带回的突触可塑性和兴奋性发生变化，由此导致胰腺局部、胃肠道和躯体痛觉敏感性升高和痛觉情绪行为的异常。在上述中枢改变过程中，前扣带回的CaMKII和AMPA数量和功能变化起关键介导作用。本研究为进一步认识慢性胰腺炎疼痛机制，寻找临床治疗靶标提供帮助。