Mechanism of Nociception Induced by Innocuous Cold in Trigeminal System

描述（由申请人提供）：口面部疼痛病症包括广泛的病症，包括三叉神经痛、面部反射性交感神经营养不良（RSD）、颞下颌关节病症、牙周疼痛、灼口综合征、牙科手术疼痛、头颈癌疼痛、口腔感染引起的疼痛以及其它神经性和炎性疼痛病症。许多慢性口面疼痛病症中的一个常见症状是冷异常性疼痛/痛觉过敏，由通常会产生无害或轻度疼痛的冷却感觉的冷却温度引起的极度疼痛感觉。不幸的是，目前的临床治疗是不令人满意的这种慢性口面疼痛的条件。这在很大程度上是由于对三叉神经感觉系统控制冷敏感性的机制了解不足。我们最近积累的证据表明，伤害性冷感受神经元的冷敏感性可能在很大程度上取决于低阈值电压门控K+通道（KLT），其是电压门控K+通道的一个亚类，在静息膜电位附近被激活。此外，我们发现，增强KLT通道逆转口面冷异常性疼痛/痛觉过敏。在此更新申请中，总体目标是研究KLT通道在生理和三叉神经病变条件下控制伤害性冷感知三叉神经元的冷敏感性中的作用，并探索KLT通道增强剂用于治疗口面冷异常性疼痛和痛觉过敏的治疗用途。先进的神经学技术，包括膜片钳记录和钙成像，以及其他方法，包括免疫染色和新的动物模型将在这个项目中使用。通过实现我们的目标，我们将确定新的治疗目标，治疗一些顽固性口面疼痛的条件。

DESCRIPTION (provided by applicant): Orofacial pain disorders encompass a wide range of conditions including trigeminal neuralgia, reflex sympathetic dystrophy (RSD) of the face, temporomandibular joint disorders, periodontal pain, burning mouth syndrome, dental surgical pain, head and neck cancer pain, pain due to oral infections, and other neuropathic and inflammatory pain conditions. One common symptom in many chronic orofacial pain conditions is cold allodynia/hyperalgesia, the excruciating painful sensation induced by cooling temperatures that would normally produce innocuous or mild painful cooling sensation. Unfortunately, the current clinical treatments are unsatisfactory for this chronic orofacial pain condition. This is largely due to the poor understanding of mechanisms for controlling cold sensitivity in trigeminal sensory system. We have recently accumulated evidence suggesting that cold sensitivity of nociceptive cold- sensing neurons may largely depend on low-threshold voltage-gated K+ channels (KLT), a subclass of voltage-gated K+ channels that are activated near resting membrane potentials. Furthermore, we found that pharmacologically potentiating KLT channels reversed orofacial cold allodynia/hyperalgesia. In this renewal application, the overall objectives are to study the role of KLT channels in controlling cold sensitivity of nociceptive cold-sensing trigeminal neurons under both physiological and trigeminal neuropathic conditions, and to explore therapeutic use of KLT channel potentiators for treating orofacial cold allodynia and hyperalgesia. Advanced neurological techniques including patch-clamp records and calcium imaging together with other approaches including immunostaining and novel animal models will be used in this project. By accomplishing our goal, we will have identified novel therapeutic targets for treating some intractable orofacial pain conditions.