Mechanisms and Treatment of Dental Pain

目前严重牙痛的治疗包括根管治疗或拔牙。获得足够的麻醉， 侵入性手术通常很困难。在多达18%的患者中观察到无法获得完全或深度麻醉。 根管治疗的注意事项结果是，相当多的患者必须承受剧烈的疼痛， 程序的持续时间。除了这种痛苦经历的一些长期有害后果外， 发炎的牙髓更难麻醉，这表明更多的局部麻醉剂（LA）将被用于努力获得一个 足够的麻醉水平，从而增加全身和/或局部毒性的可能性。而一些 虽然已经提出了LA失败的解释，但没有一个能够解释在研究中观察到的LA失败的性质和程度。 存在牙髓炎。在本申请中，我们提出测试一个新的假设，该假设涉及左心房衰竭的基础。 牙髓炎症的存在：LA衰竭是由于沿着 牙髓传入纤维的轴突。重要的是，这些变化也可能在与炎症相关的疼痛中发挥重要作用 在口腔内。我们建议在3个具体目标下描述的实验中检验这一假设，我们将： 确定牙髓炎症诱导的大鼠LA敏感性降低是否反映了生物物理学的变化， 牙髓传入纤维中VGSC亚基的性质、相对密度和/或表达模式（具体目标1）;确定是否 牙髓炎症、LA敏感性降低和VGSC相对密度变化之间存在关联 亚基在人类牙齿（具体目标2）;并评估牙髓炎症，VGSC的变化之间的因果关系的基础 亚基表达和大鼠中LA敏感性的变化（特异性目的3）。重要的是，这些实验的结果不会 这只能使我们能够确定在大鼠中观察到的变化是否可能导致人类LA失败，但将使我们能够 在亚单位表达的变化和LA失败之间建立因果关系。这些实验的结果可能不仅 能够识别使根管治疗更耐受的方法，但可能产生新的治疗方法， 用于治疗与慢性炎症和神经损伤相关的疼痛的干预措施。

Current treatment of severe dental pain includes root canal therapy or tooth extraction. Obtaining adequate anesthesia for these invasive procedures is often difficult. Failure to obtain complete, or profound anesthesia is observed in as many as 18% of patients undergoing root canal treatment. The result is that a significant number of patients must withstand intense pain for the duration of the procedure. In addition to several long-term deleterious consequences of such painful experiences, the fact that the inflamed pulp is more difficult to anesthetize suggests that more local anesthetic (LA) will be employed in an effort to obtain a sufficient level of anesthesia, thereby increasing the likelihood of systemic and/or local toxicity. Whereas a number of explanations for LA failure have been proposed, none are able to account for the nature and extent of LA failure observed in the presence of pulpitis. In the present application, we propose to test a novel hypothesis concerning the basis of LA failure in the presence of pulpal inflammation: that LA failure is due to a change in voltage-gated Na+ channel (VGSC) subunits along the axons of pulpal afferents. Importantly, these changes may also play a significant role in the pain associated with inflammation within the oral cavity. We proposed to test this hypothesis in experiments described under 3 Specific Aims in which we will: determine whether the pulpal inflammation-induced decrease in LA sensitivity in the rat reflects a change in the biophysical properties, relative density and/or pattern of expression of VGSC subunits in pulpal afferents (Specific Aim 1); determine whether there is an association between pulpal inflammation, a decrease in LA sensitivity and changes in the relative density of VGSC subunits in human teeth (Specific Aim 2); and evaluate the basis for a causal link between pulpal inflammation, changes in VGSC subunit expression and changes in LA sensitivity in the rat (Specific Aim 3). Importantly, results from these experiments will not only enable us to determine whether changes observed in the rat may contribute to LA failure in humans, but will enable us to establish a causal link between changes in subunit expression and LA failure. Results from these experiments may not only enable identification of ways to make root canal treatment a more tolerable procedure, but may yield novel therapeutic interventions for the treatment of pain associated with both chronic inflammation and nerve injury.