Cellular and molecular mechanisms of dental pain

描述（由申请人提供）：牙痛是最常见的口腔面部疼痛类型之一，但其机制仍知之甚少。了解牙痛的细胞和分子机制对于制定更好的治疗牙痛的新策略至关重要。痛觉感受器主要分为两类：肽能性痛觉感受器和非肽能性痛觉感受器。在牙髓中，已知大量的传入物具有肽能。然而，没有令人信服的证据表明ib4阳性的非肽能性事件有髓质投射。我们使用一种新的小鼠模型进行的初步研究显示，牙髓密集地受一群选择性表达Mrgprd （mass相关G蛋白偶联受体d亚型）的伤害性初级传入神经支配。由于Mrgprd阳性传入神经代表了皮肤中大多数非肽能性伤害感受器，这强烈表明牙髓中有大量的非肽能性伤害感受器投射。在这个应用中，我们将定义逆行标记三叉神经节中mrgprd阳性牙传入神经的神经化学性质，以提供ib4阳性非肽能传入神经的牙髓投射的明确证据（Aim I）。为了证明这些传入事件参与了牙齿损伤或炎症时的神经反应和潜在的疼痛，我们将证明mrgprd阳性传入事件参与了牙齿损伤时三叉神经伤害感觉回路的激活（Aim II），并研究牙齿炎症是否会增强atp诱导的mrgprd阳性牙髓伤害感受器的激活（Aim III）。这些研究将为牙齿传入神经的一个新子集提供强有力的解剖学和功能证据，并为开发针对该神经元亚群中丰富分子的潜在镇痛药物提供科学依据。

DESCRIPTION (provided by applicant): Dental pain is one of the most prevalent types of orofacial pain but its mechanism is still poorly understood. Understanding cellular and molecular mechanisms of tooth pain is critical for developing novel strategies for better treating dental pain. Nociceptors are divided into largely two populations, peptidergic nociceptors and non-peptidergic nociceptors. In tooth pulp, a large population of afferents is known to be peptidergic. However, there is no convincing evidence of a pulpal projection of IB4-positive non-peptidergic afferents. Our preliminary study using a novel mouse model revealed that tooth pulp is densely innervated by a subpopulation of nociceptive primary afferents selectively expressing Mrgprd, Mas-related G protein-coupled receptor subtype D. Since the Mrgprd-positive afferents represent a majority of non-peptidergic nociceptors in skin, it strongly suggests that tooth pulp has a profuse projection of non-peptidergic nociceptors. In this application, we will define the neurochemical properties of Mrgprd-positive dental afferents in retrogradely labeled trigeminal ganglia to provide unambiguous evidence of the pulpal projection of IB4-positive non-peptidergic afferents (Aim I). In order to demonstrate that the afferents are involved in neural responses and potentially pain upon tooth injury or inflammation, we will demonstrate the involvement of Mrgprd-positive afferents in the activation of trigeminal nociceptive circuitry upon tooth injury (Aim II) and investigate whether tooth inflammation enhances ATP-evoked activation of Mrgprd-positive pulpal nociceptors (Aim III). These studies will provide strong anatomical and functional evidence of a novel subset of dental afferents and provide the scientific rationale for developing potential analgesic agents targeting molecules enriched in this subpopulation of neurons.