Cellular and molecular mechanisms of dental pain

描述（由申请人提供）：牙痛是最常见的口面疼痛类型之一，但其机制仍然知之甚少。了解牙痛的细胞和分子机制对于开发更好地治疗牙痛的新策略至关重要。伤害感受器主要分为两个群体，肽能伤害感受器和非肽能伤害感受器。在牙髓中，已知大量的传入神经是肽能的。然而，没有令人信服的证据表明，牙髓投射的IB4阳性非肽能传入。我们使用一种新的小鼠模型的初步研究表明，牙髓是由伤害性初级传入选择性表达Mrgprd，mas相关的G蛋白偶联受体亚型D的亚群密集神经支配。由于Mrgprd阳性传入神经代表了皮肤中的大多数非肽能伤害感受器，因此强烈表明牙髓具有丰富的非肽能伤害感受器投射。在这个应用程序中，我们将定义的神经化学性质的Mrgprd阳性的牙齿传入逆行标记三叉神经节提供明确的证据，牙髓投影的IB4阳性非肽能传入（目的我）。为了证明传入参与神经反应和牙齿损伤或炎症后的潜在疼痛，我们将证明Mrgprd阳性传入参与牙齿损伤后三叉神经伤害感受回路的激活（目的II），并研究牙齿炎症是否增强ATP诱发的Mrgprd阳性牙髓伤害感受器的激活（目的III）。这些研究将提供强有力的解剖学和功能证据的一个新的子集的牙齿传入，并提供科学的理由，开发潜在的镇痛剂靶向分子富集在这个亚群的神经元。

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.