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齿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，用炎症刺激物刺激牙髓可诱导大鼠脑干和丘脑中NMDA受体（NMDAR）依赖的伤害性神经元的“中枢致敏”，脑干尾侧亚核（“髓背角”）战略性地参与了这一过程，该过程与损伤和炎症后可能发生的异常性痛觉、痛觉过敏以及疼痛的扩散和转递有关。嘌呤能受体（P2XR）机制最近被确定为脊髓伤害性传递的另一个调节过程，可能通过脊髓背角对谷氨酸释放的强大突触前调节起作用。最近，我们首次发现嘌呤能机制在口面区中枢伤害性加工中的作用。我们建议在这些发现的基础上，使用免疫细胞化学和体内和体外电生理技术来验证以下假设：A)牙髓和硬脑膜对Vc的传入输入包括表达P2XR的传入，这些传入足以通过中枢P2XR机制诱导Vc中枢致敏和相关的感觉运动行为；B)中枢P2XR对Vc的初级传入传递产生突触前促进作用，这依赖于特定的NMDAR亚基。我们的实验设计将使我们能够确定表达P2XR的传入事件，这些传入脑干的输入是否足以通过中枢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亚基起作用。这些研究将提供新的信息，新的化学介质的伤害性传递，并获得新的见解，从牙髓和硬脑膜的感觉信息的加工。这些见解可能是重要的，在发展改进的治疗方法，以预防与牙髓炎相关的疼痛和缓解疼痛，一旦它已经启动。

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.