Role of glutamate receptors to develop abnormal pain following trigeminal nerve injury in awake behaving monkeys

本项目主要进行两项研究：1)清醒行为猴子研究和2)麻醉大鼠研究。1)为了探讨三叉神经区异常疼痛的神经机制，系统应用N型钙通道阻滞剂ONO 2921对清醒行为的辣椒素致痛觉过敏猴子的影响。热探测任务在辣椒素治疗的猴子中进行训练。分别口服或经鼻膜给药N型钙，测定热检测潜伏期。使用ONO 2921后，热检测延迟明显延长。与鼻给药相比，口服给药的检测潜伏期延长稍长。施用ONO 2921后，未处理辣椒素的猴子的检测潜伏期没有明显变化。目前的研究结果表明，ONO 2921具有减少辣椒素治疗后猴子异常疼痛的有效能力。2)建立下眶神经损伤大鼠模型，研究谷氨酸受体参与三叉神经痛的机制。眶下神经损伤后大鼠对面部机械刺激的逃逸阈值降低。我们观察到离子结扎大鼠三叉神经脊髓尾侧亚核（Vc）神经元活动明显增强。AMPA受体拮抗剂CNQX引起该大鼠神经元活性显著降低，但NMDA受体拮抗剂APV或MK801未引起神经元活性降低。提示AMAP受体参与了三叉神经损伤后三叉神经异常疼痛的发生。

Two major studies were conduced in the present project, 1) awake behaving monkey study and 2) anesthetized rat study.1) In order to evaluate the neuronal mechanisms of abnormal pain in the trigeminal region, the effect of N type calcium channel blocker, ONO 2921 was systemically applied to the awake behaving monkeys with capsaicin induced hyperalgesia. The thermal detection task was trained in capsaicin treated monkeys. N type calcium was applied orally or via nasal membrane, and the thermal detection latency was measured. Heat detection latency was significantly elongated after ONO 2921 administration. The elongation of detection latency was slightly longer in oral-administrated monkeys compared with nasal-administrated monkeys. We could not any significant change in detection latency in capsaicin-untreated monkeys after ONO 2921 administration. The present results suggest that ONO 2921 have potent ability to reduce abnormal pain following capsaicin treatment in monkeys.2) The rats' model with inferior orbital nerve injury was studied how the glutamate receptors were involved in the trigeminal neuropathic pain. Rats showed reduction of escape threshold to mechanical stimulation of the face following infra-orbital nerve (ION) injury. We observed significant enhancement of neuronal activity in the trigeminal spinal subnucleus caudalis (Vc) of the rats with ION ligation. After AMPA receptor antagonist CNQX caused significant reduction of neuronal activity in this rat, but not after NMDA receptor antagonist APV or MK801 administration. These suggest that AMAP receptor is involved in trigeminal abnormal pain following trigeminal nerve injury.