Dental and Orofacial Pain: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中枢机制和神经可塑性过程。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痛觉神经元的“中枢致敏”，并且脑干尾侧亚核（“髓背角”）战略性地参与其中。NMDA受体（NMDAR）也参与了这一过程，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诊有关。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。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起作用外，还没有研究表明嘌呤能在口面区中枢伤害性加工中的机制。因此，我们提出了体内和体外实验来确定(i)纸浆诱导的尾侧伤害性神经元中枢致敏是否涉及内源性嘌呤能机制；如果是，（ii）这些机制是否为突触前机制；（iii）它们是否依赖NMDA受体。我们的实验设计将允许我们在体内测试内源性嘌呤能机制参与纸浆诱导的Vc中功能鉴定的单个神经元的中枢敏化，以及它们调节谷氨酸释放和NMDAR激活的潜力。体内实验将辅以体外实验，这将为P2XR亚型的参与以及嘌呤能受体机制是否在突触前起作用提供重要的额外见解。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，从牙髓感觉信息的中央处理。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 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.