Mechanisms and Treatment of Dental Pain

描述（申请人提供）：目前严重牙痛的治疗包括根管治疗或拔牙。为这些侵入性手术获得足够的麻醉通常是困难的。在接受根管治疗的患者中，多达18%的患者无法获得完全或深度麻醉。其结果是，相当多的患者必须在手术期间承受剧烈的疼痛。除了这种痛苦经历的几种长期有害后果之外，发炎的牙髓更难以麻醉的事实表明，为了获得足够的麻醉水平，将使用更多的局部麻醉剂（LA），从而增加全身和/或局部毒性的可能性。尽管已经提出了许多对LA失败的解释，但没有一个能够解释在牙髓炎存在下观察到的LA失败的性质和程度。在本申请中，我们提出了一个新的假设，在牙髓炎症的存在下，LA失败的基础进行测试：LA失败是由于电压门控Na+通道（VGSC）亚基的变化沿着牙髓传入轴突。重要的是，这些变化也可能在与口腔内炎症相关的疼痛中发挥重要作用。我们建议在3个特定目的下描述的实验中验证这一假设，其中我们将：确定大鼠牙髓炎症诱导的LA敏感性降低是否反映了牙髓传入纤维中VGSC亚基的生物物理性质、相对密度和/或表达模式的变化（具体目标1）;确定牙髓炎症，人牙齿中LA敏感性的降低和VGSC亚基相对密度的变化（具体目标2）;并评价大鼠牙髓炎症、VGSC亚基表达变化和LA敏感性变化之间因果关系的基础（具体目标3）。重要的是，这些实验的结果不仅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，而且使我们能够建立亚基表达变化与LA失败之间的因果关系。这些实验的结果不仅可以确定使根管治疗成为一种更可耐受的程序的方法，而且可以产生新的治疗干预措施，用于治疗与慢性炎症和神经损伤相关的疼痛。公共卫生相关性：在每年接受根管治疗的1600万美国人中，有多达18%的人在手术期间和手术后都会遭受剧烈的疼痛，因为在牙髓急性炎症的情况下，很难并且在某些情况下不可能用局部麻醉剂获得足够的麻醉水平。我们建议测试一个新的假设，即在存在发炎牙齿的情况下观察到的局部麻醉剂敏感性降低反映了支配发炎牙齿的感觉神经元中电压门控Na+通道的生物物理性质、密度和/或相对分布的变化。由于在炎症存在下观察到的VGSC的变化也可能导致与持续性炎症相关的疼痛，因此确定局部麻醉剂敏感性变化的潜在机制不仅可以实现更耐受的牙科手术，而且可以产生用于治疗与慢性炎症和神经损伤相关的疼痛的新型治疗干预。

Description (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: As many as 18% of the 16 million Americans who undergo root canal therapy every year are subjected to intense pain both during and after the procedure because it is difficult, and in some cases impossible to obtain an adequate level of anesthesia with local anesthetics in the presence of acute inflammation of the tooth pulp. We propose to test a novel hypothesis that the decrease in local anesthetic sensitivity observed in the presence of an inflamed tooth reflects a change(s) in the biophysical properties, density and/or relative distribution of voltage-gated Na+ channels in the sensory neurons that innervate the inflamed tooth. Because the changes in VGSCs observed in the presence of inflammation may also contribute to pain associated with persistent inflammation, identification of mechanisms underlying the change in local anesthetic sensitivity may not only enable more tolerable dental procedures, but may yield novel therapeutic interventions for the treatment of pain associated with both chronic inflammation and nerve injury.