Trigeminal Neuropathic Pain Mechanisms

描述（由申请人提供）：慢性神经性疼痛是一种毁灭性的疾病，治疗往往不充分。神经损伤后钠离子通道表达的变化可能导致神经元的高兴奋性和神经性疼痛的发生，这是近期疼痛研究的一个重点。本研究将在光镜和电镜下研究正常大鼠三叉神经初级传入神经（眶下神经、三叉神经节/神经根进入区和三叉神经感觉核）和三叉神经感觉核内征神经元中Nav1.1、Nav1.2、Nav1.3、Nav1.6、Nav1.7、Nav1.8和Nav1.9钠通道异构体的分布。一旦确定了每个异构体的正常表达，那么在慢性缝合损伤后的同一区域，将评估该表达的变化；1)眶下神经，或2)三叉神经根进入区，并结合行为测试来改变伤害感觉。假设损伤后钠通道同种异构体的正态分布会发生变化，这与伤害感觉改变的行为证据有关，这种变化可能取决于损伤部位（外周还是中枢），这些变化有助于损伤后原发性传入神经元和内在神经元的过度活跃，并减少钠通道阻断药物的过度兴奋性。三叉神经系统是评估周围神经或中枢神经根损伤后钠通道表达差异的一个很好的模型系统，因为在这些不同损伤后的人类中可以看到不同的临床实体。三叉神经痛可由神经根进入区损伤引起，而三叉周围神经病变是由周围神经损伤引起的。外周和中枢损伤后钠通道的表达可能存在差异，因为三叉神经痛患者通常对卡马西平有反应，而外周三叉神经病变患者仅使用卡马西平很少能明显缓解。不同纤维类型中钠通道的差异表达也可能是外周和中枢损伤后疼痛的不同临床特征的原因。损伤后特异性钠通道改变的鉴定可能有助于开发更多选择性治疗神经性疼痛的方法。

DESCRIPTION (provided by applicant): Chronic neuropathic pain can be a devastating disease and the management is often inadequate. A recent focus of pain research is examining changes in the expression of sodium channels that follow nerve injury since these changes may contribute to neuronal hyperexcitability and the development of neuropathic pain. This proposal will investigate the distributions of Nav1.1, Nav1.2, Nav1.3, Nav1.6, Nav1.7, Nav1.8 and Nav1.9 sodium channel isoforms at both the light and electron microscopic levels in normal rat trigeminal primary afferents (infraorbital nerve, trigeminal ganglion/root entry zone and trigeminal sensory nucleus) and in intrinsic neurons in the trigeminal sensory nucleus. Once the normal expression is determined for each isoform, then changes in this expression will be evaluated in the same regions following a chromic suture injury to; 1) infraorbital nerve, or 2) trigeminal root entry zone, combined with behavioral testing for altered nociception. The hypothesis is that there will be a change in the normal distribution of the sodium channel isoforms following injury that correlates with behavioral evidence for altered nociception, the changes may depend on the site of the injury (peripheral vs. central), these changes contribute to neuronal hyperactivity of both primary afferents and intrinsic neurons seen following lesions, and the reduction of hyperexcitability with sodium channel blocking drugs. The trigeminal system represents an excellent model system to evaluate differences in sodium channel expression following either peripheral nerve or central root injury since distinct clinical entities are seen in humans following these different injuries. Trigeminal neuralgia may result from a root entry zone injury, while peripheral trigeminal neuropathy follows damage to peripheral nerves. There may be a difference in the expression of sodium channels following peripheral and central injury, since patients with trigeminal neuralgia usually respond to carbamazepine, while patients with peripheral trigeminal neuropathy rarely obtain significant relief with only carbamazepine. A differential expression of sodium channels in different fiber types may also be responsible for the different clinical characteristics of pain seen following peripheral and central injury. Identification of specific sodium channel alterations after injury may help develop more selective treatments for neuropathic pain.