基于去甲肾上腺素损害联合脑DTI和肌电图的帕金森病疼痛受体效应机制研究

The mechanism of pain in Parkinson's disease(PD) is unclear, and there is no effective pain treatment currently. The loss of locus coeruleus norepinephrine(NE) neurons may play a crucial role in PD pain. Our previous studies showed that PD pain may be related to neurotransmitter NE, and may be influenced by peripheral nerve damage as well. Therefore, this study is proposed to analyze magnetic resonance diffusion tensor imaging(DTI), pain threshold and VAS score, and then confirm that PD pain is related to decreased functional connection of NE from locus coeruleus to both anterior frontal lobe and anterior cingulum. Next, we will apply a2 adrenergic receptor agonists and antagonists, and examined NE, flow of sodium ions, and activation of neurons and glial cells in both brain and spinal cord dorsal horn in PD rat model, and it will be proved that NE is involved in PD pain through a2 adrenergic receptor. Lastly, we studied the peripheral nerve conduction velocity and evoked potential in PD patients, and conclusion may be obtained that peripheral nerve damage is related to pain threshold. We will further confirm in PD rats with ligated sciatic nerves that injury signals are regulated via a2 adrenergic receptor. In conclusion, this study will confirm that decreased NE is a major cause of PD pain, and a2 adrenergic receptor could be a potential therapeutic target for PD pain management. It has important clinical significance and application prospect.

帕金森病(PD)疼痛机制不明确，缺乏有效的治疗措施，病人蓝斑去甲肾上腺素(norepinephrine,NE)神经元缺失可能是重要原因。本课题组以往研究表明PD疼痛可能与NE有关，并受周围神经损害影响。本研究拟通过磁共振弥散张量成像(DTI)结合痛阈和VAS评分，证实PD疼痛与蓝斑至前额叶和前扣带回NE功能连接减少有关；通过应用肾上腺素a2受体激动剂和抑制剂，检测PD大鼠脑和脊髓背角NE、钠离子流、神经元及胶质细胞活化，证实NE通过肾上腺素a2受体参与PD疼痛。通过检测PD病人周围神经传导速度和诱发电位明确周围神经损害与痛阈相关，并在PD大鼠坐骨神经结扎模型上证实伤害性输入信号受肾上腺素a2受体调控。本研究明确NE缺乏为PD疼痛的重要原因，并为肾上腺素a2受体作为治疗靶点提供依据，具有重要的临床意义和应用前景。

帕金森病(Parkinson’s disease, PD)疼痛机制不明确。由于PD病人蓝斑NE能神经元损失严重，并有研究证实去甲肾上腺素(norepinephrine, NE)参与病理疼痛的调控，其中α2肾上腺素能受体可能起主要作用，因而本课题对NE与PD疼痛的相关性进行研究. 对于中枢机制的研究，通过对病人的DTI成像分析显示：与PD疼痛相关的脑区有右侧顶叶、双侧枕叶、双侧前额叶白质和左侧基底前脑；相关纤维束有：丘脑-顶叶环路；丘脑-枕叶环路；丘脑-中央后回环路；纹状体-顶叶环路；纹状体-额叶-枕叶环路；纹状体-枕叶环路，并且相关部位脑血流有改变。. 建立6-OHDA诱导的PD大鼠模型(DA)和建立6-OHDA+DSP-4(或anti-DBH-saporin)诱导的模型(DA+NE)。结果显示：DA+NE组大鼠肢体的痛觉过敏加重。应用胍法辛和育亨宾后，痛阈改善。DA+NE大鼠前额叶、前扣带回的 c-Fos和GFAP 阳性细胞增加。应用胍法辛和育亨宾后GFAP 阳性率降低。DA+NE组脊髓背角的GFAP增加，c-fos明显减少。给予胍法辛和育亨宾后，脊髓背角的GFAP减少。. PD疼痛周围机制的研究。检测PD病人运动感觉传导速度。伴肢体疼痛的PD病人，痛阈与肢体运动或感觉神经损害相关。动物实验对DA组大鼠进行坐骨神经结扎(DA+SNL)，结扎后大鼠的前额叶表达GFAP和GABA阳性细胞减少，c-Fos阳性细胞增多。育亨宾腹腔内给药后，DA+SNL大鼠的c-Fos细胞减少，GFAP和GABA细胞增多。脊髓背角DA+SNL组GFAP阳性细胞反应与前额叶相同。. 结论：与PD疼痛相关的脑区和纤维较为广泛。前额叶和扣带回影响PD痛阈，并与NE相关，受肾上腺a2受体调控。周围神经损害参与PD疼痛的发生，并且也有脊髓背角和前额叶参与，并受肾上腺a2受体调控。