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由降温引起的剧烈痛感，而降温通常会产生无害或愉快的降温感觉。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刺激的感觉编码机制缺乏了解。最近，包括TRPM8、TRPA1和K2P在内的几个离子通道被认为是冷敏受体的候选通道。这项建议的总体目标是确定，在慢性口面部疼痛情况下，i)这些冷感受器候选中的哪些参与了无害的寒冷诱导的口腔面部疼痛，以及ii)哪些外周和中枢神经机制负责维持由无害的寒冷引起的慢性口腔面部疼痛。这个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，包括逆行追踪、免疫染色和动物模型。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。与公共卫生相关的口腔面部疼痛状况是一个重大的临床问题，由于对神经和分子机制缺乏了解，一直没有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确定参与无害(非疼痛)寒冷引起的口面部疼痛状态的热感受器和神经机制，这种情况见于三叉神经病和口面部其他病理疾病的患者。本项目提出的目标的实现将导致治疗某些口腔面部疼痛情况的新的治疗靶点。

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.