Cellular and molecular mechanisms of dental pain

描述(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。了解牙齿疼痛的细胞和分子机制对于开发更好地治疗牙齿疼痛的新策略至关重要。伤害性感受器主要分为两类，即肽能伤害性感受器和非肽能型伤害性感受器。在牙髓中，已知有大量的传入神经是肽能的。然而，没有令人信服的证据表明IB4阳性的非肽能传入神经元存在牙髓投射。我们用一种新的小鼠模型进行的初步研究表明，牙髓中有大量的伤害性初级传入神经元选择性地表达与Mas相关的G蛋白偶联受体D亚型。由于这些阳性传入神经元在皮肤中代表了大多数非肽能伤害性感受器，这有力地表明牙髓中有丰富的非肽能伤害性感受器的投射。在这一应用中，我们将定义三叉神经节逆行标记的MRGPrd阳性牙科传入的神经化学性质，以提供IB4阳性非肽能传入的牙髓投射的明确证据(Aim I)。为了证明神经传入参与牙齿损伤或炎症时的神经反应和潜在的疼痛，我们将演示MRGPrd阳性传入参与牙齿损伤时三叉神经伤害性环路的激活(AIM II)，并研究牙齿炎症是否增强了ATP诱导的MRGPrd阳性牙髓伤害性感受器的激活(AIM III)。这些研究将为新的牙科传入提供强有力的解剖学和功能证据，并为开发针对这一神经元亚群中丰富的分子的潜在止痛剂提供科学依据。

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.