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。在许多慢性口面疼痛病症中的一个常见症状是由通常会产生无害或愉快的冷却感觉的冷却温度引起的严重疼痛感觉。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对冷刺激的感觉编码机制认识不足。TRPM8、TRPA1和K2P等离子通道是近年来发现的冷感受受体的候选者。该提议的总体目标是在慢性口面疼痛病症中鉴定I）这些冷感应受体候选者中的哪些参与无害的冷诱导的口面疼痛，以及II）哪些外周和中枢神经元机制负责维持由无害的冷诱导的慢性口面疼痛。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，包括逆行追踪，免疫染色和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。公共卫生相关性口腔面部疼痛状况是重要的临床问题，由于对神经元和分子机制的理解不足，尚未得到令人满意的治疗。该项目将使用先进的神经生物学方法和动物模型来识别参与由无害（非疼痛）低温诱导的口面疼痛状态的热受体和神经元机制，这种情况见于三叉神经病变和口面区域其他病理性疾病的患者。该项目中提出的目标的实现将导致用于治疗某些口面疼痛状况的新的治疗靶点。

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 the severe painful sensation induced by cooling temperatures that would normally produce innocuous or pleasant cooling sensation. Unfortunately, the current clinical treatments are unsatisfactory for this chronic orofacial pain condition. This is largely due to the poor understanding of sensory coding mechanisms for cold stimuli in trigeminal sensory system. Several ion channels including TRPM8, TRPA1 and K2P have recently be proposed to be candidates of cold-sensing receptors. The overall goal of this proposal is to identify, in chronic orofacial pain conditions, I) Which of these cold-sensing receptor candidates are involved in innocuous cold- induced orofacial pain, and II) What peripheral and central neuronal mechanisms are responsible for the maintenance of chronic orofacial pain induced by innocuous cold. Advanced neurological techniques including patch-clamp records and calcium imaging together with other approaches including retrograde tracing, immunostaining and 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. PUBLIC HEALTH RELEVANCE Orofacial pain conditions are significant clinical problems that have not been treated satisfactorily due to the poor understanding of neuronal and molecular mechanisms. This project will use advanced neurobiological approaches and animal models to identify thermal receptors and neuronal mechanisms that are involved in an orofacial pain state induced by innocuous (non-painful) cold temperatures, a condition seen in patients with trigeminal neuropathy and other pathological disorders in orofacial regions. The accomplishment of the Aims proposed in this project will lead to novel therapeutic targets for treating some orofacial pain conditions.