Understanding the functional role of kappa opioid receptor signaling in somatosensory neurons

了解卡帕阿片受体信号传导在体感神经元中的功能作用

基本信息

批准号：
9258162
负责人：
Michael Chi-Chung Chiang
金额：
$ 4.9万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9258162
关键词：
Address Adverse effects Afferent Neurons Agonist American Anatomy Behavioral Behavioral Assay Biological Assay C Fiber Calcium Cells Clinical Treatment Clinical Trials Data Dorsal Drug Targeting Dynorphins Electrophysiology (science)Free Nerve Ending Human Inflammatory Knock-in Mouse Knowledge Measures Mediating Modality Molecular Mus Neuraxis Neurons Opioid Organ Pain Pain management Pathologic Pathway interactions Peripheral Pharmaceutical Preparations Physiologic pulse Physiological Property Pruritus Quality of life Receptor Signaling Regulation Research Training Role Seizures Sensory Skin Spinal Cord Stimulus System Testing Therapeutic Time Treatment Efficacy Work alternative treatment base behavior test behavioral response cellular targeting chronic itch chronic pain delta opioid receptor dorsal horn effective therapy experimental study inflammatory pain insight kappa opioid receptors medical attention neurochemistry neurotransmitter release optogenetics pain behavior patch clamp presynaptic receptor response somatosensory therapeutic target voltage

项目摘要

Chronic itch and pain are debilitating conditions that significantly decrease quality of life of millions worldwide and are primary reasons that Americans seek medical attention. Nevertheless, few treatments exist that effectively reduce itch or pain without causing severe adverse effects. This is, in part, because current therapies act on central targets whose mechanisms are poorly understood. Therefore, increasing our knowledge of the regulation of physiologic itch and pain is critical for developing safer and more effective therapies. This proposal aims to reduce this gap, thereby providing insight into the peripheral modulation of itch and pain. Our lab has previously shown that the kappa opioid dynorphin inhibits itch within the dorsal spinal cord. This effect may have been due, at least in part, to presynaptic inhibition via the action of dynorphin on primary sensory afferents in the spinal cord. I now have preliminary data indicating that peripherally selective kappa opioids may inhibit inflammatory itch and pain and reduce thermal sensitivity, suggesting a modulatory role for KOR in conveying these sensory modalities in primary afferent neurons. Therefore, I hypothesize that peripherally selective agonists will act through KOR to inhibit inflammatory itch and pain and reduce thermal sensitivity. This proposal will investigate the functional role of KOR signaling in somatosensory neurons through anatomical, electrophysiological, and behavioral approaches. I will characterize KOR-Cre+ DRG neurons to determine the molecular identity and visualize their peripheral and central projections (Aim 1); use patch-clamp electrophysiology and optogenetic strategies to analyze whether primary afferents express functional levels of KOR and whether these effects occur on peripheral terminals, central terminals, or both (Aim 2); and measure alterations in the behavioral responses to itch and pain-induced stimuli in the presence or absence of peripherally selective kappa opioids (Aim 3). These experiments will elucidate the function of KOR signaling on somatosensory neurons with the potential to identify safer, more effective therapeutic targets for chronic itch and pain.

慢性瘙痒和疼痛是一种使人衰弱的疾病，会显着降低全世界数百万人的生活质量，也是美国人寻求医疗救助的主要原因。然而，很少有治疗方法可以有效减轻瘙痒或疼痛而不引起严重的副作用。部分原因是目前的疗法作用于中心靶点，但其机制尚不清楚。因此，增加我们对生理性瘙痒和疼痛调节的了解对于开发更安全、更有效的疗法至关重要。该提案旨在缩小这一差距，从而深入了解瘙痒和疼痛的外周调节。我们的实验室此前已证明卡帕阿片类强啡肽可抑制背脊髓内的瘙痒。这种效应可能至少部分是由于强啡肽对脊髓初级感觉传入的作用而产生的突触前抑制。我现在有初步数据表明外周选择性卡帕阿片类药物可能抑制炎症瘙痒和疼痛并降低热敏感性，这表明 KOR 在初级传入神经元中传递这些感觉模式方面具有调节作用。因此，我推测外周选择性激动剂将通过 KOR 发挥作用，抑制炎症瘙痒和疼痛并降低热敏感性。该提案将通过解剖学、电生理学和行为学方法研究 KOR 信号在体感神经元中的功能作用。我将表征 KOR-Cre+ DRG 神经元以确定分子身份并可视化它们的外周和中心投影（目标 1）；使用膜片钳电生理学和光遗传学策略来分析初级传入神经是否表达 KOR 的功能水平以及这些影响是否发生在外周末梢、中枢末梢或两者上（目标 2）；并测量在存在或不存在外周选择性卡帕阿片类药物的情况下对瘙痒和疼痛引起的刺激的行为反应的变化（目标 3）。这些实验将阐明 KOR 信号在体感神经元上的功能，并有可能确定更安全、更有效的慢性瘙痒和疼痛治疗靶点。