Dental and Craniofacial Pain: Afferent and Brainstem Mechanisms

描述（由申请人提供）：这项由NIH支持的研究计划的长期目标是阐明急性和慢性牙齿和口面疼痛及其控制的机制和神经可塑性过程。我们最近的数据表明，用炎症刺激物刺激牙髓可诱导大鼠脑干和丘脑中伤害性神经元的NMDA受体（NMDAR）依赖性“中枢敏化”，脊髓背角（“髓背角”）在策略上参与了这一过程，该过程涉及异常性疼痛、痛觉过敏以及可能在损伤和炎症后发生的疼痛的扩散和转移。嘌呤能受体（P2 XR）机制是脊髓伤害性信息传递的另一个调节过程，可能通过突触前调节脊髓背角谷氨酸的释放发挥作用。最近，我们提供了嘌呤能机制在口面区域中枢伤害性处理中的作用的第一个发现。我们建议建立在这些发现的基础上，并使用免疫细胞化学和在体内和体外电生理技术来验证假设：A）来自牙髓和硬脑膜的Vc传入输入包括表达P2 XR的传入，其足以通过中枢P2 XR机制诱导Vc中枢敏化和相关的感觉运动行为;和B）中枢P2 XR产生依赖于特定NMDAR亚基的Vc中初级传入传递的突触前易化。我们的实验设计将使我们能够确定表达P2 XR的传入，如果这些传入脑干的输入足以通过中枢P2 XR机制诱导中枢敏化，如果中枢P2 XR突触前促进初级传入传递并通过NMDAR亚基起作用。这些研究将为伤害性传递的新型化学介质提供新的信息，并将获得对牙髓和硬脑膜感觉信息处理的新见解。这些见解可能是重要的，在发展中国家的改善治疗方法，预防疼痛与牙髓炎症和缓解疼痛，一旦它已经开始。

DESCRIPTION (provided by applicant): This NIH-supported research program has the long-term objective of elucidating the mechanisms and neuroplastic processes underlying acute and chronic dental and orofacial pain conditions and their control. Our recent data indicate that stimulation of the tooth pulp with an inflammatory irritant induces a NMDA receptor(NMDAR)-dependent 'central sensitization' of nociceptive neurons in the rat brainstem and thalamus and that the brainstem subnucleus caudalis ('medullary dorsal horn') is strategically involved in this process that has been implicated in the allodynia, hyperalgesia and spread and referral of pain that may occur after injury and inflammation. Purinergic receptor (P2XR) mechanisms have been recently identified as another modulatory process in spinal nociceptive transmission that may function through a powerful presynaptic regulation of glutamate release in the spinal dorsal horn. Recently, we have provided the first findings of a role for purinergic mechanisms in central nociceptive processing in the orofacial region. We propose to build upon these findings and use immunocytochemical and in vivo and in vitro electrophysiological techniques to test the hypotheses A) Afferent inputs to Vc from tooth pulp and dura include P2XR-expressing afferents that are sufficient to induce Vc central sensitization and associated sensorimotor behavior by central P2XR mechanisms; and B) Central P2XR produce a presynaptic facilitation of primary afferent transmission in Vc that is dependent on specific NMDAR subunits. Our experimental design will allow us to determine the afferents expressing P2XR, if these afferent inputs to brainstem are sufficient to induce central sensitization by central P2XR mechanisms, and if central P2XR presynaptically facilitate primary afferent transmission and act via NMDAR subunits. These studies will provide new information on a novel chemical mediator of nociceptive transmission, and new insights will be gained of the processing of sensory information from the tooth pulp and dura. These insights could be important in the development of improved therapeutic approaches for the prevention of pain associated with pulpal inflammation and for the relief of pain once it has been initiated.