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Adenylyl cyclase signaling in persistent pain

持续性疼痛中的腺苷酸环化酶信号传导

基本信息

批准号：
10418657
负责人：
DEREK C MOLLIVER
金额：
$ 45.99万
依托单位：
UNIVERSITY OF NEW ENGLAND
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10418657
关键词：
A kinase anchoring protein Acute Acute Pain Adenylate Cyclase Affect Afferent Neurons American Analgesics Animals Arthritis Automobile Driving Behavior assessment Behavioral Biochemical Brain CRISPR/Cas technology Cells Cessation of life Chronic Clinical Co-Immunoprecipitations Complex Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Dangerousness Development Diabetic Neuropathies Dinoprostone Electrophysiology (science)Family Family member G Protein-Coupled Receptor Signaling Gene Deletion Genes Goals Hyperalgesia Hypersensitivity Image Immunohistochemistry In Vitro Inflammatory Injury Intervention Intractable Pain Investigation Ion Channel Ion Channel Gating Knock-out Knockout Mice Lead Malignant Neoplasms Mass Spectrum Analysis Mechanics Mediating Modeling Molecular Mus Neurogenic Inflammation Neurons Neuropathy Neuropeptides Nociception Nociceptors Opioid Opioid Analgesics Opioid Receptor Pain Pain management Pathologic Peripheral Persistent pain Pharmaceutical Preparations Pharmacology Phosphoproteins Phosphorylation Play Postherpetic neuralgia Pre-Clinical Model Production Protein Isoforms Receptors, Adrenergic, alpha-2 Regulation Reporter Resistance Role Scaffolding Protein Second Messenger Systems Signal Pathway Signal Transduction Signaling Protein Spinal Cord Spinal Ganglia Sustainable Development Syndrome System TRPV1 gene Testing Western Blotting allodynia base chronic pain chronic pain management clinically significant effective intervention effective therapy experimental study improved in vivo innovation non-opioid analgesic novel pain chronification patch clamp prescription opioid receptor recruit response scaffold societal costs transmission process

项目摘要

Chronic pain affects more than 50 million Americans per year, resulting in extraordinary personal and societal costs. Adding to the dilemma, deaths involving prescription opiate analgesics have almost quadrupled in the last ten years. The clinical challenge of pain management is underscored by evidence that chronic pain is mechanistically distinct from acute pain, therefore a thorough understanding of the molecular and cellular mechanisms underlying the transition to chronic pain is fundamental to improving and expanding treatment options. Hyperalgesic priming is a compelling model of the transition to chronic pain in which an initial injury resolves, but leaves the animal in a primed state in which a second insult induces a greatly prolonged pain response. While previous studies have explored the development of sustained mechanical hypersensitivity, we have adapted this model to examine sustained hypersensitivity mediated by nociceptors expressing the heat-gated ion channel TRPV1, which can drive pain in a range of inflammatory and neuropathic conditions. Experiments proposed here will test the contribution to heat hyperalgesic priming of adenylyl cyclase isoform AC2, which has not been previously characterized in sensory neurons, and which is insensitive to inhibition by Gi/o-coupled receptors such as opioid receptors. Preliminary analysis indicates that AC2 is highly expressed in TRPV1-expressing neurons and required for the manifestation of heat hyperalgesic priming. Specific Aim 1 will examine the impact of AC2 gene deletion and pharmacological inhibition on behavioral nociceptive thresholds at baseline, in acute hyperalgesia and in the setting of hyperalgesic priming. Specific Aim 2 will determine whether AC2 and the downstream effector Epac are functionally coupled through AKAP family member scaffolding proteins by co-immunoprecipitation-mass spectrometry, and will determine the impact of deleting identified AKAP genes on Epac signaling and nociceptor function in vitro using a CRISPR/Cas9-based approach. Specific Aim 3 will determine the consequences for Epac function of AC2 and AKAP gene deletion through Epac-dependent PKC phospho- substrate profiling and behavioral assessment of heat hyperalgesia. This proposal will use innovative approaches to explore novel mechanisms contributing to the development of persistent hyperalgesia.

每年有超过5000万美国人受到慢性疼痛的影响