Central Neural Mechanisms of Itch

瘙痒的中枢神经机制

• 批准号: 7762400
• 负责人: GLENN JOSEPH GIESLER
• 金额: $ 30.63万
• 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/7762400
• 关键词: Adverse effects; Affect; Afferent Neurons; Analgesics; Antihistamines; Area; Axon; Brain; Capsaicin; Cathepsins; Cell Nucleus; Cerebral cortex; Chronic; Circumscribed Lesion; Clinical; Complex; Disease; Esthesia; Funding; GABA Antagonists; Glycine; Histamine; Injection of therapeutic agent; Inpatients; Instruction; Insula of Reil; Lateral; Lateral posterior nucleus of thalamus; Mediating; Methods; Modeling; Monkeys; Morphine; Neuraxis; Neurons; Nociception; Nociceptive Stimulus; Opiates; Pain; Pathway interactions; Patients; Peptide Hydrolases; Population; Posterior Thalamic Nuclei; Primates; Principal Investigator; Process; Production; Pruritus; Public Health; Role; Sensory Process; Site; Skin; Spinal; Spinal Cord; Spinothalamic Tracts; Stimulus; System; Systemic disease; Techniques; Testing; Thalamic structure; Thoracic spinal cord structure; chronic pain; effective therapy; insight; intradermal injection; midbrain central gray substance; neuromechanism; neurophysiology; novel therapeutic intervention; receptive field; research study; response; spinal cord white matter; transmission process; white matter

Itch associated with several conditions can be effectively treated with antihistamines. However itch caused by many conditions, including relatively common dermatological disorders and systemic diseases, can not. These latter types of itch constitute a considerable clinical problem since no effective treatment is currently available. During the previous period of funding, our group has shown that separate populations of primate spinothalamic tract (STT) neurons respond to the itch-producing stimuli intradermal injections of histamine and cowhage, a model of clinically important, non-histaminergic itch. Our results suggest that separate pathways within the CNS carry information regarding histaminergic and non-histaminergic forms of itch. In experiments under Specific Aim 1, we will determine the effects on STT neurons of application of histamine, cowhage, capsaicin, or cathepsin S. These studies will determine whether there are two, or more, distinct pruriceptive pathways within the primate STT. We have also recently found that scratching the receptive fields of STT neurons during a response to histamine inhibited the response for several seconds, mirroring the relief produced by scratching an itchy area of skin. Studies under Specific Aim 2 will determine whether the scratching induced inhibition is dependent solely upon circuitry within the spinal cord or whether there are also important contributions from the brain. Administration of morphine inpatients frequently produces severe itch. This side effect can limit the amount of morphine given to treat chronic pain . Under Specific Aim 3, we will determine whether iontophoretically applied morphine activates pruriceptive and inhibits non- pruriceptive (nociceptive) STT neurons. Our results using antidromic activation techniques revealed that pruriceptive primate STT axons project to several specific nuclei within the posterior thalamus. Under Specific Aim 4, we will record the responses of neurons in these thalamic areas to histamine injections or applications of cowhage. We will identify cortical projection sites of pruriceptive thalamic neurons using antidromic activation. These studies will provide important new information on the processing itch-related information in both the thalamus and cerebral cortex. RELEVANCE (See instructions): The proposed neurophysiological experiments will further our understanding of how itch and pain sensations are mediated by the responses of different types of sensory neurons in the spinal cord and the brain. This will benefit public health by identification of sensory processes in the central nervous system that must be modified pharmacologically in patients suffering from chronic itch or pain.

与多种病症相关的瘙痒可以用抗组胺药有效治疗。然而瘙痒引起 受许多条件影响，包括相对常见的皮肤病和全身性疾病，不能。 由于目前尚无有效的治疗方法，后一种类型的瘙痒构成了相当大的临床问题。 可用的。在上一个资助期间，我们的小组已经证明，灵长类动物的不同种群 脊髓丘脑束（STT）神经元对皮内注射组胺产生瘙痒的刺激有反应 和牛皮，一种临床上重要的非组胺性瘙痒模型。我们的结果表明，单独 中枢神经系统内的通路携带有关组胺能和非组胺能瘙痒形式的信息。在 具体目标 1 下的实验，我们将确定应用组胺对 STT 神经元的影响， 牛、辣椒素或组织蛋白酶 S。这些研究将确定是否存在两种或多种不同的 灵长类动物 STT 内的瘙痒通路。我们最近还发现，抓挠感受器 在对组胺做出反应期间，STT 神经元的场会抑制该反应几秒钟，这与 通过抓挠皮肤发​​痒的部位而产生的缓解效果。具体目标 2 下的研究将确定是否 抓挠引起的抑制仅取决于脊髓内的电路或是否存在 也是大脑的重要贡献。住院患者服用吗啡经常会产生 严重瘙痒。这种副作用会限制治疗慢性疼痛的吗啡用量。在特定目标下 3，我们将确定离子电渗疗法应用吗啡是否会激活瘙痒并抑制非 瘙痒性（伤害性）STT 神经元。我们使用逆向激活技术的结果表明 瘙痒性灵长类 STT 轴突投射到后丘脑内的几个特定核。在下面 具体目标4，我们将记录这些丘脑区域的神经元对组胺注射或 牛犊的应用。我们将使用以下方法识别丘脑瘙痒神经元的皮质投射位点 逆向激活。这些研究将为处理与瘙痒相关的过程提供重要的新信息。 丘脑和大脑皮层的信息。 相关性（参见说明）： 拟议的神经生理学实验将进一步我们对瘙痒和疼痛感觉的理解 由脊髓和大脑中不同类型的感觉神经元的反应介导。这 通过识别中枢神经系统中的感觉过程，将有利于公众健康，而这些过程必须是 对患有慢性瘙痒或疼痛的患者进行药理学改良。