Mechanism of Nociception Induced by Innocuous Cold in Trigeminal System

描述(申请人提供)：口腔面部疼痛障碍包括多种疾病，包括三叉神经痛、面部反射性交感神经营养不良(RSD)、颞下颌关节紊乱病、牙周疼痛、灼口综合征、牙科手术疼痛、头颈部癌症疼痛、口腔感染引起的疼痛，以及其他神经性和炎症性疼痛。许多慢性口腔面部疼痛的一个常见症状是冷痛感/痛觉过敏，这是一种由降温引起的极度疼痛的感觉，通常会产生无害或轻微的疼痛降温感觉。不幸的是，目前的临床治疗方法对这种慢性口面部疼痛状况并不令人满意。这在很大程度上是由于对三叉神经感觉系统中冷敏感性的控制机制缺乏了解。我们最近积累的证据表明，伤害性冷感神经元的冷敏感性可能在很大程度上依赖于低阈值电压门控K通道(KLT)，KLT是电压门控K通道的一个亚类，在静息膜电位附近激活。此外，我们还发现，药理上增强的KLT通道逆转了口面部冷痛/痛敏。在这一新的应用中，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三叉神经神经元冷敏感性的作用，并探索KLT通道增强剂在治疗口面部冷痛和痛觉过敏中的应用。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，将被用于这个项目。通过实现我们的目标，我们将为治疗一些顽固性口腔面部疼痛疾病确定新的治疗靶点。

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.