杏仁核NMDA受体参与神经病理性疼痛相关情绪形成的机理

Neuropathic pain is a type of chronic pain that develops from lesions or dysfunction in the nervous system. Many studies and interventions have focused on the spinal cord level, but the efficacy of treating neuropathic pain is to date unsatisfactory. As many patients suffering from neuropathic pain usually have affective- motivational pain responses, the aim of this study is to investigate the relationship between the affective-motivational dimension of pain and the changes in the supraspinal region. It has been suggested that the NMDA (N-methyl-D-aspartate) receptors is involved in the initiation and maintenance of neuropathic pain. In addition, amygdala is a center of affective modulation in the central nervous system and it has anatomic associations with pain-related brain regions. Therefore, we hypothesize that the NMDA receptors in amygdala might be associated with the affective-motivational pain responses in neuropathic pain condition. To test the hypothesis, a rat model of chronic constriction injury (CCI) will be used to induce neuropathic pain and a paradigm that reflecting the motivational-affective aspect of pain will also be established in this study. The expression of different types of NMDAR in the amygdala will be examined by immunofluorescence and Western blot to elucidate the relationship between the NMDAR in amygdale and the pain behaviors. Furthermore, the changes of pain behaviors will be assess after stereotaxic injection of specific NMDA receptor antagonists into amygdala to valid our hypothesis. This study may provide an alternative research approach in studying neuropathic pain and may provide a new direction of therapeutic intervention in the future

神经病理性疼痛是一种由神经系统损伤而产生的慢性疼痛。针对脊髓水平的研究至今仍不足以解释临床症状及提供有效治疗方案。考虑患者多出现与疼痛相关的情绪改变，本项目重点研究神经性痛相关的情绪变化与脊髓以上结构变化的关系。既往研究证实脊髓N-甲基-D-天冬氨酸受体（NMDAR）参与其机制，而杏仁核是机体的情绪整合中枢并与许多疼痛相关的脑区相连，可能参与疼痛相关情绪的形成。因此，本项目选择杏仁核为研究靶点，旨在明确杏仁核内不同亚型的NMDAR是否参与调控神经性痛相关情绪的形成。本项目拟采用新的行为学指标-逃避厌恶情绪测试，并通过分子生物学、组织学技术，明确NMDAR在杏仁核内的分布及表达水平在神经损伤后是否发生改变，并应用脑立体定位微量注射药物对杏仁核内NMDAR表达进行直接干预，结合其行为学改变，从正反两方向证实杏仁核内NMDAR参与神经病理性疼痛相关情绪形成，将开辟新的研究思路并提供新的治疗方向

由神经系统损伤而产生的慢性疼痛称为神经病理性疼痛，既往的实验多针对脊髓水平而进行研究，但至目前为止仍不足以解释临床症状且无法提供有效的治疗方案。临床上，患者多出现与疼痛相关的情绪改变，因此本项目重点研究神经性痛相关的情绪变化以及其与脊髓以上结构变化的关系。之前的研究表明，脊髓的N-甲基-D-天冬氨酸受体（NMDAR）参与慢性疼痛的发生和发展，而杏仁核是机体的情绪整合中枢并与许多疼痛相关的脑区相连，可能参与疼痛相关情绪的形成，其内在机制尚不明确。本项目以杏仁核为研究靶点，探讨不同亚型的NMDAR是否参与调控神经性痛相关情绪的形成。我们的研究首先建立了可靠的坐骨神经损伤（CCI）及测试逃避厌恶情绪的模型，证实在坐骨神经损伤后，同侧大鼠后足出现痛觉超敏，且出现逃避厌恶情绪的反应，采用免疫荧光、免疫印迹等多种方法探讨了杏仁核内NR2A及NR2B在损伤后的表达情况。并在此基础上应用脑立体定位微量注射NR2A及NR2B拮抗剂对杏仁核内的NMDAR表达进行直接干预，结合其行为学改变与NR2A及NR2B在两侧杏仁核内的表达，我们发现NR2A与痛觉超敏及厌恶情绪的形成有关，而NR2B与仅与厌恶情绪的形成有关