Neural Mechanisms of Itch

瘙痒的神经机制

• 批准号: 8111286
• 负责人: ROBERT H LA MOTTE
• 金额: $ 119.22万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111286
• 关键词: Neural; Mechanisms; Itch

DESCRIPTION (provided by applicant): The neural basis of Itch is poorly understood despite its importance as a primary quality of cutaneous sensation and as a clinical symptom of many neurological and other disorders. During our previous funding period we discovered that itch is mediated by subpopulations of nociceptive primary neurons and nociceptive spinothalamic tract (STT) neurons, some responsive to histamine, and others to the spicules of cowhage that evoked a histamine independent itch via a novel cysteine protease that we identified. We devised a precise method of eliciting pruritic and nociceptive chemically evoked sensations (dysesthesias) by using chemically inert (heat inactivated) spicules soaked in an endogenous cysteine protease, histamine, or capsaicin. We propose to continue our combined, psychophysical and neurophysiological study of itch requiring the integrated efforts of three different projects each using a different experimental approach. Project 1 will measure psychophysically the itch, nociceptive sensations and dysesthesias evoked by heat-inactivated cowhage spicules containing histamine, capsaicin or an endogenous cysteine protease. The effects of mechanical, thermal or chemical stimuli in enhancing or suppressing itch and the effects of blocking conduction in myelinated nerve fibers will be examined to reveal underlying neural mechanisms controlling itch. Project 2 will electrophysiologically record the responses, to the same stimuli used in project 1, of peripheral nerve fibers in monkey to determine the separate contributions of nociceptive neurons with myelinated vs. non-myelinated axons to itch and nociceptive sensations and to the enhancement and inhibition of itch. Project 3 will electrophysiologically record the responses of STT- and thalamic neurons to the same stimuli used in projects 1 & 2. In addition, the effects of iontophoretic application of morphine, a GABA inhibitor, and the blocking of descending pathways from suprasegmental areas on STT neuronal responses will reveal spinal mechanisms of the enhancement and inhibition of itch, nociception and pruritic dysesthesias. A core providing administration, instrumentation, statistics and informatics will facilitate the collection, analysis and evaluation of the data obtained from each project. By increasing our understanding of the peripheral and central neural mechanisms that code and modulate itch and nociceptive sensations, our combined studies will provide new targets for novel therapies to relieve itch and pain. Public Health Relevance: The proposed psychophysical and neurophysiological studies of experimentally produced itch and pain will advance our understanding of how these sensations are mediated by sensory neurons in the peripheral and central nervous system. Identification of these neurons and their properties will provide targets for pharmacological therapies to relieve chronic itch and pain in humans.

描述（由申请人提供）：瘙痒的神经基础知之甚少，尽管其重要性是皮肤感觉的主要质量，也是许多神经系统和其他疾病的临床症状。在以前的资金期间，我们发现瘙痒是由伤害感受性原发性神经元和伤害性脊柱刺丘脑（STT）神经元的亚群介导的，一些神经元，有些对组胺有反应，而另一些对乳壳的反应，这些神经元通过新颖的囊泡蛋白酶独立于我们所识别的canamine Indch而唤起了组胺独立的鸡肉。我们通过使用化学惰性（热灭活的）在内源性半胱氨酸蛋白酶，组胺或辣椒蛋白中使用化学惰性（热灭活的）spicules，设计了一种精确的方法来诱导促尿液和伤害性化学诱发感觉（感染性）。我们建议继续对瘙痒进行组合，心理物理和神经生理研究，要求使用不同的实验方法进行三个不同项目的综合努力。项目1将通过心理物理测量含有组胺，辣椒素或内源性半胱氨酸蛋白酶的热灭活的乳头spicules诱发的瘙痒，伤害感受感和发抖。机械，热或化学刺激对增强或抑制瘙痒的影响以及髓鞘纤维中阻断传导的影响将检查以揭示控制瘙痒的基本神经机制。项目2将在电生理上记录猴子周围神经纤维中使用的相同刺激的反应，以确定具有髓鞘轴承与非膜的轴突对瘙痒和伤害性感觉以及增强和抑制ITCH的伤害感受神经元的单独贡献。 Project 3 will electrophysiologically record the responses of STT- and thalamic neurons to the same stimuli used in projects 1 & 2. In addition, the effects of iontophoretic application of morphine, a GABA inhibitor, and the blocking of descending pathways from suprasegmental areas on STT neuronal responses will reveal spinal mechanisms of the enhancement and inhibition of itch, nociception and pruritic失调。提供管理，仪器，统计和信息学的核心将有助于从每个项目获得的数据收集，分析和评估。通过对我们对编码并调节瘙痒和伤害感受感觉的外围和中心神经机制的理解，我们的合并研究将为减轻瘙痒和疼痛的新疗法提供新的靶标。 公共卫生相关性：实验性产生和疼痛的拟议的心理物理和神经生理研究将使我们对这些感觉如何由外周和中枢神经系统中的感觉神经元介导。这些神经元及其特性的识别将为药物疗法提供靶标，以缓解人类的慢性瘙痒和疼痛。