Dental and Orofacial Pain: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中枢机制和神经可塑性过程。最近的数据表明，刺激牙髓的炎症刺激诱导的伤害性神经元在大鼠脑干和丘脑的“中枢敏化”和脑干亚核尾侧（“髓背角”）的战略参与。NMDA受体（NMDAR）也参与了这一过程，这一过程与损伤和炎症后可能发生的异常性疼痛、痛觉过敏以及疼痛的扩散和转移有关。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。除了我们实验室最近的一些初步数据间接表明这些机制可能在尾侧肌起作用外，还没有关于口面区域中枢伤害性处理中嘌呤能机制的研究。因此，我们建议在体内和体外实验，以确定（i）如果纸浆引起的中央敏化尾侧伤害性神经元涉及内源性嘌呤能机制;如果是这样，（ii）这些机制是否是突触前;和（iii）他们是否是NMDA受体依赖性。我们的实验设计将使我们能够在体内测试的参与内源性嘌呤能机制在纸浆诱导的中央敏化功能确定的单个神经元在Vc和其潜在的谷氨酸释放和NMDAR激活的调节。体内实验将补充体外实验，这将提供重要的额外的见解P2 XR亚型参与和嘌呤能受体机制是否运作突触前。这些研究将为伤害性传递的新型化学介质提供新的信息，并将获得牙髓感觉信息的中央处理的新见解。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 central mechanisms and neuroplastic processes underlying acute and chronic dental and orofacial pain conditions and their control. Recent data indicate that stimulation of the tooth pulp with an inflammatory irritant induces a 'central sensitization' of nociceptive neurons in the rat brainstem and thalamus and that the brainstem subnucleus caudalis ('medullary dorsal horn') is strategically involved. NMDA receptors (NMDAR) are also 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. There has been no study of purinergic mechanisms in central nociceptive processing in the orofacial region, other than some recent preliminary data from our laboratory that indirectly suggests these mechanisms may operate in caudalis. We therefore propose in vivo and in vitro experiments to determine (i) if the pulp-induced central sensitization in caudalis nociceptive neurons involves endogenous purinergic mechanisms; if so, (ii) whether these mechanisms are presynaptic; and (iii) whether they are NMDA receptor dependent. Our experimental design will allow us to test in vivo the involvement of endogenous purinergic mechanisms in pulp-induced central sensitization in functionally identified single neurons in Vc and their potential for regulation of glutamate release and NMDAR activation. The in vivo experiments will be supplemented by in vitro experiments that will provide important additional insights into the P2XR subtype involved and whether the purinergic receptor mechanisms are operating presynaptically. These studies will provide new information on a novel chemical mediator of nociceptive transmission, and new insights will be gained of the central processing of sensory information from the tooth pulp. 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.