Dental and Craniofacial Pain: Afferent and Brainstem Mechanisms

描述(由申请人提供)：这项由美国国立卫生研究院支持的研究项目的长期目标是阐明急性和慢性牙科和口腔面部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，炎症刺激物刺激牙髓可以诱导大鼠脑干和丘脑中依赖NMDAR的伤害性神经元的中枢敏化，脑干尾侧亚核(延髓背角)参与了这一过程，这一过程与损伤和炎症后可能发生的痛觉过敏、痛觉过敏以及疼痛的扩散和转介有关。嘌呤能受体(P2XR)是脊髓伤害性信息传递的另一种调节机制，可能通过突触前调节脊髓背角谷氨酸的释放而发挥作用。最近，我们首次发现了嘌呤能机制在口腔面部中枢伤害性信息处理中的作用。我们建议在这些发现的基础上，使用免疫细胞化学和体内、体外电生理技术来检验假设：A)从牙髓和硬脑膜到VC的传入输入包括足以通过中枢P2XR机制诱导VC中枢敏化和相关感觉运动行为的P2XR表达的传入；以及B)中枢P2XR产生依赖于特定NMDAR亚单位的Vc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P2XR的传入，如果这些传入到脑干的传入足以通过中枢P2XR机制诱导中枢敏化，以及中枢P2XR是否在突触前促进初级传入传递并通过NMDAR亚单位起作用。这些研究将为伤害性信息传递的一种新的化学媒介提供新的信息，并将对牙髓和硬脑膜的感觉信息的处理获得新的见解。这些见解可能对开发改进的治疗方法以预防牙髓炎症相关的疼痛并在疼痛开始后缓解疼痛具有重要意义。

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.