TRPV1 Modulation during Craniofacial Neuropathy and its Contribution to Chronic Pain

颅面神经病变期间 TRPV1 的调节及其对慢性疼痛的影响

• 批准号: 9396991
• 负责人: John Joseph
• 金额: $ 3.84万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-12 至 2019-07-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9396991
• 关键词: Acute; Attenuated; Award; Behavioral Assay; Biological Assay; C57BL/6 Mouse; Calcium; Caliber; Capsaicin; Cells; Chronic; Clinical Trials; Control Groups; Craniofacial Pain; Development; Electrophysiology (science); Facial Nerve Injuries; Fiber; Goals; Hyperalgesia; Image; Immunohistochemistry; Injury; Isolectin; Knock-in Mouse; Knockout Mice; Label; Lead; Maintenance; Mechanics; Modeling; Molecular; Mus; Nerve; Neurons; Neuropathy; Nociception; Nociceptors; Orofacial Pain; Pain; Phosphorylation; Phosphorylation Site; Plasticizers; Prevention; Process; Property; Protein Kinase C; Reporter; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Serotonin; Signal Transduction; Site; Structure of trigeminal ganglion; Testing; Therapeutic; Tomatoes; Trigeminal Neuralgia; Trigeminal System; Up-Regulation; Vanilloid; Western Blotting; attenuation; career; chronic constriction injury; chronic pain; constriction; craniofacial; design; experimental study; in vivo; interdisciplinary approach; nerve injury; neurochemistry; novel; novel therapeutic intervention; orofacial; painful neuropathy; preference; receptor; response; sensory system; sham surgery; skills; voltage clamp

Project Summary Maladies such as trigeminal neuralgia are of neuropathic origin and lead to chronic pain. The detailed processes of increased nociceptive signaling leading to chronic pain are obscure. Recently a novel role for the transient receptor potential vanilloid-1 (TRPV1) has been demonstrated for mechanical hyperalgesia (excessive pain response), using a nerve-injury model for chronic orofacial pain. The study provides evidence for increased response of TRPV1 at central nociceptive terminals when activated (sensitization). Its selective inhibition alleviated mechanical hyperalgesia acutely. The sensitization was shown to be facilitated by serotonin, yet the means by which TRPV1 becomes sensitized is undetermined. Furthermore, during nerve constriction injury TRPV1 expression is reportedly increased. The functional sensitivity (and relevance) of this supplementary TRPV1 has yet to be evaluated in the trigeminal sensory system. The goal of this study is to clarify the detailed cellular and molecular mechanisms whereby TRPV1 contributes to craniofacial neuropathic pain. We hypothesize chronic pain following infraorbital nerve-chronic constriction injury (ION-CCI) is associated with plastic changes in expression or function of TRPV1 in trigeminal nociceptors. This hypothesis will be tested by multidisciplinary approaches as outlined in three aims. In aim 1, we will assess the role of TRPV1 in development and maintenance of craniofacial neuropathic pain. In aim 2, we will determine neurochemical and functional properties of TRPV1-expressing nociceptors in trigeminal ganglia following craniofacial neuropathy. In aim 3, we will determine the contribution of TRPV1 phosphorylation to chronic pain following craniofacial neuropathy. Our study offers a thorough assessment for the contribution of TRPV1 to chronic orofacial neuropathic pain, and thus potentially validates it as a therapeutic mark. It critically examines the in vivo significance for PKC phosphorylation of TRPV1, thereby resolving a proposed mechanism for its increased sensitivity. This award should provide the opportunity to develop the applicant’s career as a young investigator for further research of orofacial pain.

项目摘要 诸如三叉神经痛之类的疾病是神经性的起源，导致慢性疼痛。 增加伤害感受信号的详细过程导致慢性疼痛是晦涩的。 最近，瞬时受体电势香草素-1（TRPV1）的新作用已经 使用神经伤害证明了机械性痛觉过敏（过度疼痛反应） 慢性口面痛的模型。该研究提供了增加TRPV1响应的证据 在激活时（敏化）时中央伤害终端。它的选择性抑制可缓解 机械痛觉过敏。灵敏度证明是通过5-羟色胺制备的， 然而，trpv1变得敏感的手段尚不确定。此外，期间 据报道，神经收缩损伤TRPV1表达增加。功能灵敏度 该补充TRPV1的（和相关性）尚未在三叉神经感觉中进行评估 系统。这项研究的目的是阐明详细的细胞和分子机制 TRPV1导致颅面神经性疼痛。我们假设慢性疼痛 在肌肌肌颈神经 - 颅骨狭窄损伤（ION-CCI）之后与塑料有关 Trpv1在三叉神经伤害感受器中的表达或功能的变化。这个假设将是 通过三个目标中概述的多学科方法测试。在AIM 1中，我们将评估 TRPV1在颅面神经性疼痛的发育和维持中的作用。在AIM 2中，我们 将确定表达TRPV1的伤害感受器的神经化学和功能特性 颅面神经病后的三叉神经节。在AIM 3中，我们将确定贡献 颅面神经病后，TRPV1磷酸化对慢性疼痛的磷酸化。我们的研究提供了 彻底评估TRPV1对慢性口面神经性疼痛的贡献，并 这有可能将其验证为治疗标记。它严格检查体内意义 对于TRPV1的PKC辐射，从而解决了提出的机制以增加 灵敏度。该奖项应为发展申请人的职业提供机会 年轻的研究者对口面疼痛的进一步研究。