Rodent model to distinguish between facial itch and pain

区分面部瘙痒和疼痛的啮齿动物模型

• 批准号: 7970969
• 负责人: EARL E CARSTENS
• 金额: $ 19.07万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-16 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7970969
• 关键词: Address; Afferent Neurons; Agonist; Animals; Antihistamines; Antipruritics; Area; Behavior; Biomechanics; Capsaicin; Cheek structure; Chemicals; Chronic; Clinical; Clinical Treatment; Development; Dose; Exhibits; Face; Forelimb; Formalin; Hindlimb; Histamine; Human; Injection of therapeutic agent; Ipsilateral; Kidney; Liver diseases; Mediator of activation protein; Methods; Microinjections; Modality; Modeling; Morphine; Motor; Movement; Mus; Narcotic Antagonists; Neck; Neurons; Opioid Receptor; PAR-2 Receptor; Pain; Pharmaceutical Preparations; Process; Rattus; Resistance; Rodent Model; Sensory; Sensory Process; Serotonin; Serotonin Agonists; Signal Pathway; Signal Transduction; Site; Skin; Stimulus; Systemic disease; Testing; Time; Topical application; Translations; Trigeminal System; cellular targeting; improved; in vivo; mustard oil; neuromechanism; novel; public health relevance; receptive field; relating to nervous system; response; transmission process

DESCRIPTION (provided by applicant): Chronic itch is a significant clinical problem associated with many dermatological conditions and systemic kidney and liver disease. Most forms of chronic itch are resistant to antihistamine treatment. A better understanding of itch mechanisms is urgently needed to identify cellular targets for development of novel anti-itch treatments. We propose a rodent model that distinguishes between itch and pain. Itch is usually assessed by hindlimb scratching directed toward a site of application of itch mediators in the nape of the neck of rats or mice. However, because of biomechanical limitations, the only response available to the animal is directed movement of the hindlimb to the stimulus site. Therefore, a drawback of the method is that other sensory qualities besides itch are likely to elicit scratching. In a new model involving stimulation of the cheek, at least two motor responses are available: hindlimb scratches and forelimb wipes directed to the stimulus site. Intradermal cheek injection of histamine, which is itchy to humans, elicits almost exclusively hindlimb scratching in rats and mice. In contrast, capsaicin, which is painful, elicits almost exclusively ipsilateral forelimb wiping. We propose to rigorously test if these distinct responses distinguish between itch and pain, and to investigate the neural processing of these sensory qualities. Thus, specific aim 1 will test if a variety of itch-producing chemicals selectively elicit facial scratching with the hindlimb, and if various pain-producing chemicals selectively elicit facial wiping with the forelimb. This aim will also test if scratching is reduced by drugs that block 5-opioid receptors but not by morphine, and if wiping is reduced by morphine but not by drugs blocking 5-opioid receptors. Specific aim 2 will investigate underlying neural mechanisms by recording responses of second-order trigeminal neurons to itch- and pain-evoking stimuli delivered the facial skin receptive field. We will test the hypothesis that itch- signaling neurons respond to itchy chemicals over a time course matching that of facial scratching behavior. Finally, specific aim 3 will exploit this model to investigate sensitization of itch-signaling pathways under conditions of chronic itch produced by dry facial skin. We will test the hypothesis that itchy chemicals will elicit greater scratching, while pain-evoking chemicals will elicit scratching instead of wiping due to a modality switch from pain to itch in sensitized itch-signaling pathways. An improved understanding of facial itch and pain mechanisms will provide targets for the development of means to interrupt itch and pain transmission, with great potential for translation to clinical treatment of these common conditions. PUBLIC HEALTH RELEVANCE: Chronic itch is a significant clinical problem associated with many dermatological conditions and systemic diseases, and is usually resistant to antihistamine treatment. This project will investigate a rodent model that distinguishes between facial itch and pain, and will address the underlying neural mechanisms. The project will improve our understanding of itch mechanisms and identify cellular targets for translational development of new treatments for itch and pain.

描述（由申请人提供）：慢性瘙痒是与许多皮肤病和全身性肾脏和肝脏疾病相关的重要临床问题。大多数形式的慢性瘙痒对抗组织胺治疗有抵抗力。迫切需要更好地了解瘙痒机制，以确定开发新的止痒治疗的细胞靶点。我们提出了一个啮齿动物模型，区分瘙痒和疼痛。瘙痒通常通过对大鼠或小鼠颈背中瘙痒介质的施用部位进行后肢搔抓来评估。然而，由于生物力学的限制，动物唯一可用的反应是将后肢定向运动到刺激部位。因此，该方法的缺点是除了瘙痒之外的其他感觉品质可能引起抓挠。在一个涉及刺激脸颊的新模型中，至少有两种运动反应可用：后肢抓挠和前肢擦拭刺激部位。皮内颊部注射组胺，这是发痒的人，eliminated几乎完全后肢抓挠大鼠和小鼠。与此相反，辣椒素，这是痛苦的，electrically几乎完全同侧前肢擦拭。我们建议严格测试，如果这些不同的反应区分瘙痒和疼痛，并调查这些感觉品质的神经处理。因此，具体目标1将测试各种致痒化学物质是否选择性地引起后肢的面部抓挠，以及各种致痛化学物质是否选择性地引起前肢的面部擦拭。这一目标还将测试是否通过阻断5-阿片受体的药物而不是吗啡来减少抓挠，以及是否通过吗啡而不是阻断5-阿片受体的药物来减少擦拭。具体目标2将通过记录第二级三叉神经元对传递到面部皮肤感受野的引起瘙痒和疼痛的刺激的反应来研究潜在的神经机制。我们将检验这样一个假设，即瘙痒信号神经元对瘙痒化学物质的反应与面部抓挠行为的时间过程相匹配。最后，具体目标3将利用该模型来研究在由干燥面部皮肤产生的慢性瘙痒条件下瘙痒信号传导通路的致敏作用。我们将测试的假设，发痒的化学物质会引起更大的抓挠，而疼痛诱发的化学物质会引起抓挠，而不是擦拭，由于在致敏瘙痒信号通路的模式切换从疼痛到瘙痒。对面部瘙痒和疼痛机制的更好理解将为开发中断瘙痒和疼痛传播的方法提供目标，具有转化为这些常见疾病的临床治疗的巨大潜力。 公共卫生关系：慢性瘙痒是与许多皮肤病和全身性疾病相关的重要临床问题，并且通常对抗组胺治疗具有抗性。该项目将研究区分面部瘙痒和疼痛的啮齿动物模型，并将解决潜在的神经机制。该项目将提高我们对瘙痒机制的理解，并确定用于瘙痒和疼痛新疗法翻译开发的细胞靶点。