Mechanism of Nociception Induced by Innocuous Cold in Trigeminal System

描述（由申请人提供）：口腔面部疼痛疾病包括广泛的情况，包括三叉神经痛、面部反射性交感神经营养不良（RSD）、颞下颌关节疾病、牙周痛、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他神经性和炎症性疼痛。在许多慢性口面部疼痛条件下的一个常见症状是冷异常性痛觉/痛觉过敏，由通常会产生无害或轻度疼痛的冷却感的冷却温度引起的剧烈疼痛感。不幸的是，目前的临床治疗不能令人满意的慢性口腔面部疼痛状况。这在很大程度上是由于对三叉感觉系统冷敏感性控制机制的认识不足。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取决于低阈值电压门控K+通道（KLT），这是电压门控K+通道的一个亚类，在静息膜电位附近被激活。此外，我们发现药理学上增强KLT通道逆转口面部冷异常性痛/痛觉过敏。本研究的目的是研究KLT通道在生理和三叉神经病变条件下控制痛觉性冷感三叉神经细胞冷敏感性中的作用，并探讨KLT通道增强剂治疗口面部冷异常性痛和痛觉过敏的疗效。该项目将使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，包括免疫染色和新型动物模型。通过完成我们的目标，我们将确定治疗一些顽固性口面部疼痛的新治疗靶点。

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.