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The role of the nociceptor endocytosis in inflammatory pain

伤害感受器内吞作用在炎性疼痛中的作用

基本信息

批准号：
10512357
负责人：
Arindam Bhattacharjee
金额：
$ 37.74万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10512357
关键词：
14-3-3 Family Absence of pain sensation Acute Adaptor Protein Complex 2 Adaptor Protein Complex Subunits Adaptor Signaling Protein Adrenal Cortex Hormones Adverse effects Analgesics Arthralgia Arthritis Axon Binding Biochemical Biological Assay Cartilage Cell Fractionation Chronic Chronic inflammatory pain Clathrin Clinical Treatment Complex Cyclic AMP-Dependent Protein Kinases Data Dense Core Vesicle Development Drug Targeting Endocytosis Endocytosis Inhibition Fiber Future Genes Genetic Glucocorticoids Goals Histology Human Image Impairment Inflammation Inflammatory Injections Injury Intra-Articular Injections Joints Maintenance Measures Mediating Methods Modeling Molecular Mus Mutagenesis Neurons Nociception Nociceptors Outcome Pain Patients Peptides Peripheral Pharmaceutical Preparations Pharmacology Play Protein Family Protein Kinase C Proteins Rattus Reflex action Regulation Role Saline Signal Transduction Site Spinal Ganglia Steroid therapy Stress Structure Substance P TRPV1 gene Technology Testing Therapeutic Triamcinolone Work adverse drug reaction animal pain antagonist arthritic pain arthritis therapy chronic pain coping druggable target in vivo inflammatory pain inhibitor knock-down member microCT novel opioid overuse opioid use osteoarthritis pain pain behavior pain model pain reduction pain relief pain signal preservation prevent protein expression recruit residence response side effect trafficking treatment strategy vesicle transport

项目摘要

Project Summary The current pain killer crisis, fueled by the overuse of opioids to manage chronic inflammatory pain, urges the development of non-addictive pain relief medications. Local injection of drugs, at the site of injury, is one way to circumvent adverse drug reactions, including diversion potential. For example, injection of corticosteroids into arthritic joints is one of the mainstay therapeutic approaches to treat arthritic pain, circumventing opioid use. However, recent studies have put into question their efficacy and point to potential long-term deleterious effects of steroid therapy for arthritis. Thus, we require further identification of analgesic targets specifically at nociceptive peripheral terminals, i.e. local targets. We have recently identified the adaptin 2 alpha 2 subunit Ap2A2 and nociceptor endocytosis as promising targets for pain reduction in recoverable acute and chronic animal pain models. We showed that AP2A2 binds to KNa channels to cause their internalization and precipitate dorsal root ganglion (DRG) neuronal hyperexcitability after protein kinase A stimulation. The AP2A2 subunit localized to CGRP+/IB4- nociceptors. Genetically knocking down AP2A2 or locally inhibiting endocytosis with a lipidated decoy peptide provided prolonged reductions in pain behaviors in mouse and rats during inflammatory pain. We showed that nociceptor endocytosis was required for both the development and maintenance of inflammatory pain. Our exciting new preliminary data indicates that the AP2A2 subunit localizes to large dense core vesicles and are transported down axons where the AP2A2 subunit eventually finds residence at peripheral terminals. The first Aim of this study is to further understand the subcellular localization of AP2A2 and other members of the AP2 complex in peptidergic nociceptors. We will also study their expression during chronic pain. In the second Aim, we will test the contribution of AP2A2 and nociceptor endocytosis to pain in a non-recoverable inflammatory pain model: the monoiodoacetate-induced osteoarthritic pain model. We will use a genetic knockdown approach and intraarticular injection of our lipidated AP2 inhibitor peptide to study the consequences of nociceptor endocytosis inhibition on pain behaviors. Maintenance of inflammatory pain has been shown to be dependent upon protein kinase C (PKC) signaling. We had previously shown that Slack KNa channels constitutively associate with the 14-3-3 family of proteins in DRG neurons. Our preliminary data indicates that 14-3-3 zeta causes PKC-dependent Slack KNa channel internalization. In Aim 3 we will test the hypothesis that 14-3-3 proteins confer additional endocytotic motifs to KNa channels important for inflammatory signaling. We will use a novel lipidated 14-3-3 uncoupler peptide to study KNa channel trafficking in DRG neurons and pain behavior. Positive outcomes should establish the central role of nociceptor endocytosis to inflammatory pain and reveal druggable targets.

项目摘要目前的止痛药危机，由过度使用阿片类药物来控制慢性炎症性疼痛所引发，促使开发非成瘾性止痛药物。在受伤部位局部注射药物是一种方法避免药物不良反应，包括转移的可能性。例如，注射皮质类固醇进入关节炎关节是治疗关节炎疼痛的主要治疗方法之一，可以绕过阿片类药物使用.然而，最近的研究对其有效性提出了质疑，并指出了潜在的长期有害作用。类固醇治疗关节炎的效果。因此，我们需要进一步确定镇痛靶点，伤害性外周末梢，即局部靶标。我们最近发现了适应素2 α 2亚基 Ap 2A 2和伤害性感受器内吞作用是减轻可恢复的急性和慢性疼痛的有希望的靶点动物疼痛模型我们发现，AP 2A 2与KNa通道结合，导致其内化，在蛋白激酶A刺激后沉淀背根神经节（DRG）神经元过度兴奋。AP2A2 亚基定位于CGRP+/IB 4-伤害感受器。基因敲除AP 2A 2或局部抑制脂质化诱饵肽的内吞作用在小鼠和大鼠中提供了延长的疼痛行为减少在炎性疼痛期间。我们发现伤害感受器的内吞作用是发育和维持炎性疼痛。我们令人兴奋的新的初步数据表明，AP 2A 2亚基定位于大而致密的核心囊泡，并沿轴突向下运输，在外围终端找到住所。本研究的第一个目的是进一步了解亚细胞 AP 2A 2和AP 2复合物的其他成员在肽能伤害感受器中的定位。我们还将研究在慢性疼痛中的表达。在第二个目的中，我们将测试AP 2A 2和伤害感受器的贡献。在不可恢复的炎性疼痛模型中对疼痛的内吞作用：单碘乙酸诱导的骨关节炎疼痛模型我们将使用基因敲除方法和关节内注射我们的脂化AP 2抑制剂肽来研究伤害感受器内吞作用抑制对疼痛行为的后果。维护已经显示炎性疼痛依赖于蛋白激酶C（PKC）信号传导。我们之前显示Slack KNa通道与DRG神经元中14-3-3蛋白家族组成性相关。我们初步数据表明14-3-3 ζ引起PKC依赖性Slack KNa通道内化。目标3 我们将检验14-3-3蛋白赋予KNa通道额外的内吞基序的假设，用于炎症信号传导。我们将使用一种新型脂化14-3-3解偶联肽来研究KNa通道 DRG神经元的运输和疼痛行为。积极的结果应该确立伤害感受器的核心作用内吞作用于炎性疼痛并揭示可药物化的靶点。