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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：
10634680
负责人：
Arindam Bhattacharjee
金额：
$ 38.3万
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/10634680
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 Hyperthermia 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 Play Protein Family Protein Kinase C Proteins Rattus Regulation Role Saline Signal Transduction Site Spinal Ganglia Steroid therapy Stress Structure Substance P TRPV1 gene Technology Testing Therapeutic Triamcinolone Work X-Ray Computed Tomography 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 pharmacologic preservation prevent protein expression recruit residence response side effect trafficking treatment strategy

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.

项目总结