Neural Mechanisms of Itch

描述(由申请人提供)：瘙痒的神经基础尚不清楚，尽管它是皮肤感觉的主要特征，也是许多神经和其他疾病的临床症状。在我们之前的资助期间，我们发现瘙痒是由伤害性初级神经元和伤害性脊丘脑束(STT)神经元亚群介导的，其中一些对组胺有反应，另一些则通过我们鉴定的一种新的半胱氨酸蛋白酶引起组胺非依赖性瘙痒。我们设计了一种精确的方法，通过使用浸泡在内源性半胱氨酸蛋白酶、组胺或辣椒素中的化学惰性(热失活)针叶来诱发瘙痒和伤害性感觉(感觉障碍)。我们建议继续我们对瘙痒的联合、心理物理和神经生理学研究，需要三个不同项目的综合努力，每个项目使用不同的实验方法。项目1将对含有组胺、辣椒素或内源性半胱氨酸蛋白酶的热灭活母牛针叶引起的瘙痒、伤害性感觉和感觉障碍进行心理物理测量。本课程将研究机械、热或化学刺激在增强或抑制瘙痒方面的作用，以及阻断有髓神经纤维传导的作用，以揭示控制瘙痒的潜在神经机制。项目2将记录猴子周围神经纤维对项目1中使用的相同刺激的反应，以确定具有有髓轴突和非有髓轴突的伤害性神经元对瘙痒和伤害性感觉以及对瘙痒的增强和抑制的不同贡献。项目3将记录STT神经元和丘脑神经元对项目1和2中使用的相同刺激的反应。此外，离子导入应用GABA抑制剂吗啡，以及阻断节段上区域的下行通路对STT神经元反应的影响，将揭示增强和抑制瘙痒、伤害性和瘙痒性感觉障碍的脊髓机制。一个提供行政、仪器、统计和信息学的核心将有助于收集、分析和评价从每个项目获得的数据。通过增加我们对编码和调节瘙痒和伤害性感觉的外周和中枢神经机制的了解，我们的联合研究将为缓解瘙痒和疼痛的新疗法提供新的靶点。 公共卫生相关性：拟议的对实验产生的瘙痒和疼痛的心理物理和神经生理学研究将促进我们对这些感觉是如何由外周和中枢神经系统中的感觉神经元介导的理解。对这些神经元及其特性的鉴定将为缓解人类慢性瘙痒和疼痛的药物治疗提供靶点。

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.